Ashley Dean Smith BAppSc(Physiotherapy)

Transcription

1 Whiplash Associated Disorders: A Prospective Investigation of the Effects of Cervical Medial Branch Radiofrequency Neurotomy on Sensory, Motor and Psychological Features Ashley Dean Smith BAppSc(Physiotherapy) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2014 School of Health and Rehabilitation Sciences - 1 -

2 Abstract Whiplash injury results in persistent pain and disability for a significant number of individuals. Clinically, these individuals present with a complex presentation of physical features (including central hyperexcitability and motor dysfunction) and psychological manifestations (e.g. psychological distress, pain catastrophization and posttraumatic stress symptoms) that may be resistant to conservative care. Understanding this complex symptom presentation is made challenging by the inability of current diagnostic imaging techniques to clearly identify potential pathoanatomical causes for these symptoms. Nevertheless, anatomical structures contributing to chronic whiplash associated disorders (WAD) have been identified in clinical and basic science research. Diagnostic facet joint injections implicate the cervical facet joint as the most likely anatomical structure responsible for neck pain in individuals with chronic WAD. Basic science research has also provided empirical evidence of a possible association between nociception in the cervical facet joints and the clinical features of WAD, in particular behavioural hypersensitivity (quantified pain response following stimulation with a nonnoxious stimulus). Individuals with cervical facet joint-mediated pain respond favourably to radiofrequency neurotomy (RFN), with significant reductions in neck pain and psychological distress. Yet it is unknown whether persistent cervical facet joint nociception contributes to the clinical features evident in individuals with chronic WAD, and whether effective modulation of this nociception through RFN improves these features. There has been no detailed study of the relationship between cervical facet joint nociception and the variety of clinical features demonstrated in individuals with chronic WAD. The primary aim of this thesis was to determine if the physical and psychological manifestations of chronic WAD could be effectively modulated through successful response to RFN. The null hypothesis was that reducing nociception via successful RFN would not result in improvements in central nociceptive processing, motor function or psychological features of chronic WAD. A series of studies was undertaken to test the hypothesis for this body of research. Data were collected using a range of clinical psychophysical, physical and psychological tests pertinent to chronic WAD: thermal and pressure pain thresholds (PPT), nociceptive - 2 -

3 reflex threshold (NFR), cervical range of movement (ROM) and cranio-cervical flexion test (CCFT); and questionnaires of self-reported pain (visual analogue scale: VAS) and disability (neck disability index: NDI), general well being (general health questionnaire (GHQ-28), pain catastrophization (PCS) and psychological distress (Post Traumatic Stress Diagnostic Scale: PDS). Study 1 compared the outcome of these tests between participants, aged years, who successfully responded to diagnostic facet joint injections (n=58); individuals who did not respond (n=32), and healthy controls (n=30). The results demonstrated no differences in clinical features between those who responded and did not respond to cervical facet joint injections, with both groups significantly differing from the healthy controls. Both WAD groups demonstrated generalized sensory hyperexcitability, loss of neck ROM and increased sternocleidomastoid muscle activity during the CCFT, and similar psychological features, although increased pain catastrophizing was evident in the group who did not respond to the facet injections. Studies 2-4 focussed on the individuals who responded to diagnostic facet joint blockade and proceeded to RFN. For these studies, participants attended the research laboratory at two time periods prior to RFN (after the diagnostic facet joint injections had been performed when original symptoms returned: t(1); and then immediately prior to RFN being performed approximately 12 months later: t(2)); and then at one- (t(3)) and three-months (t(4)) post-rfn and finally when pain returned (t(5)). The clinical measurements were taken at each time point. The results indicated that following RFN, most physical and psychological measures improved significantly, apart from post traumatic stress symptoms (Study 2 and 3). Upon the subsequent return of the participants neck pain, most physical (except PPTs and CCFT electromyography) and psychological measures returned to pre-rfn values (Study 4). Study 5 investigated whether any physical or psychological clinical manifestations predicted a successful response (defined as a Global Rating of Change questionnaire score of 4) to RFN. The results of this study indicated that lower levels of disability or pain catastrophizing independently predicted a successful response. The null hypothesis for this body of research was rejected. The results suggested that peripheral nociception contributes to central hyperexcitability, motor dysfunction and - 3 -

4 psychological manifestations (except post-traumatic stress symptoms) of chronic WAD. These results provide further knowledge of processes underlying chronic WAD. The finding that peripheral nociception is one of the drivers of central hyperexcitability, motor dysfunction and psychological manifestations in chronic WAD is a vital step forward towards more effective management for this difficult patient group, allowing healthcare providers to provide patients with appropriate treatment options, especially when conservative therapy has failed

5 Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the General Award Rules of The University of Queensland, immediately made available for research and study in accordance with the Copyright Act I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis

6 Publications During Candidature Peer Reviewed Journals: First Author Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. A Comparison of Physical and Psychological Features of Responders and Non-Responders to Cervical Facet Blocks in Chronic Whiplash. BMC Musculoskel Disorders, Nov 4; 14(1):313 doi: / Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Cervical Radiofrequency Neurotomy Reduces Central Hyperexcitability and Improves Neck Movement in Individuals with Chronic Whiplash. Pain Med, 2014;15(1): doi: /pme Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Dunne-Proctor R, Sterling M. Cervical Radiofrequency Neurotomy Reduces Psychological Features in Individuals with Chronic Whiplash. Pain Physician May-Jun;17(3): PMID: Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Low Pain Catastrophization and Disability Predicts Successful Outcome to Radiofrequency Neurotomy in Individuals with Chronic Whiplash (Accepted for Publication. Pain Practice. November 2, 2014) Submitted for Publication: First Author Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Modulation of Cervical Facet Joint Nociception and Pain Attenuates Physical and Psychological Features of Chronic Whiplash: A Prospective Study (Submitted August 15, 2014) Conference Abstracts: First Author Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. Sensory Hypersensitivity in Whiplash Associated Disorder: The Development of a Human Model to Determine the Presence of Hypersensitivity Following Confirmed Facet Joint Injury. Poster. 12 th World Congress on Pain. Glasgow, UK. Aug 17-22,

7 Smith A, Schneider G, Schneider K, Fonstad P. Chronic Whiplash Associated Disorders: Is a cure possible after six months? The role of physiotherapy within a multidisciplinary, primary care centre. The Role of RadioFrequency Neurotomy in Chronic Whiplash and Associated Disorders Patient. Physiotherapy Canada, 2009: 61 (Supplement 1/June 2009): 48. doi: /physio.61.abstracts Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. The Presence of Sensory Hypersensitivity in Responders to Cervical Facet Joint Double Block Procedure. Poster. 13 th World Congress on Pain. Montreal, Canada. Aug 29-Sep 2, 2010 Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. Responders and Non- Responders of Cervical Facet Blocks for Chronic Whiplash Show Similar Physical and Psychological Features Canadian Physiotherapy Association National Congress Meeting (Abstract) Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. Cervical Radiofrequency Neurotomy Reduces Widespread Sensory Hypersensitivity in Persistent WAD. Pain Medicine, 2012: 16 AUG 2012 DOI: /j x (2012 International Spinal Intervention Society Meeting Abstract) Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. Reducing Peripheral Nociception in Individuals with Chronic Whiplash, Following Cervical Radiofrequency Neurotomy, Results in Immediate Reduction in Sensory Hypersensitivity and Psychological Distress. Poster. 14 th World Congress on Pain. Milan, Italy. Aug 27-31, 2012 Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. Radiofrequency Neurotomy Results in Immediate Improvements in Physical Impairments in Individuals With Chronic Whiplash Symptoms. JOSPT, 2012: 42(10): A53-4 (American Physical Therapy Association Combined Sections Meeting Abstract) Smith A, Sterling M, Jull G, Schneider G, Frizzell B, Hooper A. Cervical radiofrequency neurotomy improves physical impairments, including sensory hypersensitivity in persistent Whiplash Associated Disorder. JOSPT, 2013: 43(1): A125 (American Physical Therapy Association Combined Sections Meeting Abstract) - 7 -

8 Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Cervical Radiofrequency Neurotomy Reduces Psychological Distress and Pain Catastrophization, but Not Post-Traumatic Stress in Individuals with Chronic WAD. Pain Res Manag, 2013: 18(2): Mar/Apr: e13 (2012 Canadian Pain Society Meeting Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Cervical Facet Joint Nociception Modulates Physical Features of Chronic Whiplash Symptoms Canadian Physiotherapy Asssociation National Congress Meeting (Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Cervical Facet Joint Nociception Modulates Physical and Psychological Features of Chronic Whiplash Symptoms Australian Physiotherapy Association Meeting (Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Physical and Psychological Features of Chronic Whiplash Symptoms Are Modulated by Cervical Radiofrequency Neurotomy. JOSPT, 2014: 44(1): A (American Physical Therapy Association Combined Sections Meeting Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. The Presence of Post- Traumatic Stress Disorder Symptoms Does Not Influence Response to Cervical Radiofrequency Neurotomy. J Pain, 2014: 15(4): S73 (2014 American Pain Society Meeting Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Individuals with Chronic Whiplash Displaying Widespread Sensory Hypersensitivity Successfully Respond to Cervical Radiofrequency Neurotomy. Pain Res Manag, 2014: 19(3): May/Jun: 124 (2014 Canadian Pain Society Meeting Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Low Levels of Pain Catastrophization Predicts Success of Cervical Radiofrequency Neurotomy in Individuals with Chronic Whiplash Symptoms. Pain Med, 2014; 15(8):1444 (2014 International Spinal Intervention Society Meeting Abstract) Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Individuals with Chronic Whiplash Displaying Widespread Sensory Hypersensitivity Successfully Respond to Cervical Radiofrequency Neurotomy Canadian Physiotherapy Association National Congress Meeting (Abstract) - 8 -

9 Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. A Time Course of Physical and Psychological Features Pre/post Cervical Radiofrequency Neurotomy in Individuals with Whiplash Injury A Prospective Study. Poster. 15 th World Congress on Pain. Buenos Aires, Argentina. Oct 6-11, Conference Publications: Co-Author Schneider G, Smith A. Causation The Chicken or the Egg? : Epidemiological Aspects of Whiplash Associated Disorders for Physiotherapists in the Medical Legal Setting. Physiotherapy Canada, 2010: 62 (Supplement 2010): doi: /ptc.62.supp Walton D, Smith A, Sterling M. Properties of the SLANSS Tool for Assessment and Prognosis in Whiplash Canadian Physiotherapy Association National Congress Meeting (Abstract) Walton D, Smith A, Sterling M. "The slanss as an Assessment and Prognostic Tool. A Psychometric Evaluation. Poster. Fourth International Congress on Neuropathic Pain, Toronto, Canada, May 23-26, 2013 Publications included in this thesis Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. A Comparison of Physical and Psychological Features of Responders and Non-Responders to Cervical Facet Blocks in Chronic Whiplash. BMC Musculoskel Disorders, Nov 4; 14(1):313 doi: /

10 This paper was incorporated as Chapter 4. Contributor Statement of contribution Ashley Smith (Candidate) Designed experiments (60%) Statistical Analysis (100%) Wrote the paper (70%) Gwen Jull Designed experiments (10%) Wrote and edited paper (10%) Geoff Schneider Designed experiments (10%) Edited paper (2%) Bevan Frizzell Designed experiments (5%) Edited paper (2%) Allen Hooper Designed experiments (5%) Edited paper (1%) Michele Sterling Designed experiments (10%) Wrote and edited paper (15%)

11 Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Cervical Radiofrequency Neurotomy Reduces Central Hyperexcitability and Improves Neck Movement in Individuals with Chronic Whiplash. Pain Med, 2014;15(1): doi: /pme This paper was incorporated as Chapter 5.1. Contributor Statement of contribution Ashley Smith (Candidate) Designed experiments (60%) Statistical Analysis (100%) Wrote the paper (70%) Gwen Jull Designed experiments (10%) Wrote and edited paper (10%) Geoff Schneider Designed experiments (10%) Edited paper (2%) Bevan Frizzell Designed experiments (5%) Edited paper (2%) Allen Hooper Designed experiments (5%) Edited paper (1%) Michele Sterling Designed experiments (10%) Wrote and edited paper (15%)

12 Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Dunne-Proctor R, Sterling M. Cervical Radiofrequency Neurotomy Reduces Psychological Features in Individuals with Chronic WAD. Pain Physician (Submitted for Publication: September 15, 2013; Accepted February 2, 2014) This paper was incorporated as Chapter 5.2. Contributor Statement of contribution Ashley Smith (Candidate) Designed experiments (60%) Statistical Analysis (100%) Wrote the paper (70%) Gwen Jull Designed experiments (10%) Wrote and edited paper (5%) Geoff Schneider Designed experiments (10%) Edited paper (2%) Bevan Frizzell Designed experiments (5%) Edited paper (2%) Allen Hooper Designed experiments (5%) Edited paper (1%) Rachael Dunne-Proctor Wrote and edited paper (5%) Michele Sterling Designed experiments (10%) Wrote and edited paper (15%)

13 Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Modulation of Cervical Facet Joint Nociception and Pain Attenuates Physical and Psychological Features of Chronic Whiplash: A Prospective Study (Submitted August 15, 2014) This paper was incorporated as Chapter 6. Contributor Statement of contribution Ashley Smith (Candidate) Designed experiments (60%) Statistical Analysis (100%) Wrote the paper (70%) Gwen Jull Designed experiments (10%) Wrote and edited paper (10%) Geoff Schneider Designed experiments (10%) Edited paper (2%) Bevan Frizzell Designed experiments (5%) Edited paper (2%) Allen Hooper Designed experiments (5%) Edited paper (1%) Michele Sterling Designed experiments (10%) Wrote and edited paper (15%)

14 Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Low Pain Catastrophization and Disability Predicts Successful Outcome to Radiofrequency Neurotomy in Individuals with Chronic Whiplash (Accepted for Publication: Pain Practice. Nov 2, 2014) This paper was incorporated as Chapter 7. Contributor Statement of contribution Ashley Smith (Candidate) Designed experiments (60%) Statistical Analysis (100%) Wrote the paper (65%) Gwen Jull Designed experiments (10%) Wrote and edited paper (15%) Geoff Schneider Designed experiments (10%) Edited paper (2%) Bevan Frizzell Designed experiments (5%) Edited paper (2%) Allen Hooper Designed experiments (5%) Edited paper (1%) Michele Sterling Designed experiments (10%) Wrote and edited paper (15%)

15 Contributions by others to the thesis No contribution by others. Statement of parts of the thesis submitted to qualify for the award of another degree None

16 Acknowledgements There are many people that I would like to thank and acknowledge for their contribution and support during my doctoral studies. A special thank you to the 120 subjects who participated in our studies. Thank you also to every one of my patients for asking the right questions to inspire me to help and know more. None of this could have been possible without their insight. Thanks must also be extended to the staff and students at the University of Queensland for their willingness to support and assist me during my trips to Brisbane. To my parents Trevor & Julie Smith thanks for providing the drive to do your best and to always keep learning. All those hours of observation of dedicated parents that wanted the best for their loving family rubbed off! A big expression of thanks goes out to my brother, Jason, who continues to inspire me as he takes life on, and believes in me. To Dr. Geoff Schneider you re an inspiration, and a credit to the profession. Thanks for your professional assistance right through this process but thanks for listening and thanks mostly for being a friend! Keep up the good work! Similarly, Dr. Kathryn Schneider you are a marvel I really appreciate all your support and dialogue to inspire. To Dr. Allen Hooper and Dr. Bevan Frizzell. Thank you so much for believing in me, and physiotherapists in general and for your vision to work as a team you re both incredible mentors as professionals, and possess such integrity as men in society. Thanks for sharing life! To Dr. James Elliott thanks for leading the way. Your advice and assistance throughout this journey has been a blessing. Thanks most of all for your warm and inviting friendship that you and your wonderful family have extended to me. I look forward to future collaborations

17 To the physiotherapy contractors and front desk staff at Evidence Sport and Spinal Therapy who have endured my ups and downs during this process thanks for your support, encouragement and patience. Thanks to the wonderful staff at EFW Radiology who assisted with patient recruitment with such enthusiasm and for assisting in providing such quality of care for my patients you go out of your way, and I appreciate it! To Mimi Chiu, Susan Saretsky, Daryl Christophe, Dr. Alex McKee and Geoff Cuskelly thanks for trusting and supporting my career in Canada with your incredible friendship and work ethics/business values. Thanks for your ears! To Lorrie Maffey a special thank you to a special friend who has listened, supported, guided, inspired and befriended my family. May God Bless you and your family always for the contributions you make to the lives you touch! To my Canadian parents, Bob and Lucille thanks for all the support and invaluable life advice and friendship. To Meaghan Buisson I ll forever by grateful for your ability to recruit subjects to complete this. Thank you for your kindness and assistance. To Professor Gwen Jull. I appreciate every piece of time you have dedicated to me. Your encouragement and support has been invaluable. Thanks for your patience and insights into this process and encouragement along the way, but also for showing me how this fits in to physiotherapy generally ( The Big Picture ). Your dedication to the physiotherapy profession is without parallel and I will be forever indebted for you taking me on at UQ and your continual guidance. To Professor Michele Sterling without your initial publications this was never going to be possible. You have inspired me along this path. You continue to be patient and understanding and utterly supportive throughout this entire time. Thanks for inspiring physiotherapy to move forwards in new directions. You have incredible talents as an international researcher and writer, and I continue to be inspired by your work but thanks for your friendship throughout this process, and for sharing at all times during this journey. I look forward to future collaborations

18 To my Champ and Blossom. Isaiah (9) and Rebecca (7) have grown up with me during this time. Thanks for loving Daddy and being patient. I look forward to answering your question of How much work have you got Daddy, with the frequent answer of None let s play. I love you both more than you can imagine. And finally, my truest love and biggest support my beautiful and inspiring wife Dorinda. You re the glue that holds our family together and allowed me to pursue this in a way that keeps our family home such a loving one nothing can fully express my gratitude and support. Thank you for sharing my dreams and coming along on this life journey. I am truly blessed by the Lord to have had the opportunity to share life with you. I look forward to our future together with so much joy and excitement. I love you dearly!

19 Keywords whiplash, cervical facet joint, radiofrequency neurotomy, pain, sensory hypersensitivity, central hyperexcitability, psychology, post traumatic stress disorder, pain catastrophization Australian and New Zealand Standard Research Classifications (ANZSRC) ANZSRC code: , Orthopaedics, 20% ANZSRC code: , Rehabilitation and Therapy (excl. Physiotherapy), 20% ANZSRC code: , Clinical Sciences not elsewhere classified, 60% Fields of Research (FoR) Classification FoR code: 1103, Clinical Sciences, 100%

20 Table of Contents ABSTRACT... 2 DECLARATION BY AUTHOR... 5 PUBLICATIONS DURING CANDIDATURE... 6 PEER REVIEWED JOURNALS: FIRST AUTHOR...6 SUBMITTED FOR PUBLICATION: FIRST AUTHOR...6 CONFERENCE ABSTRACTS: FIRST AUTHOR...6 CONFERENCE PUBLICATIONS: CO-AUTHOR...9 PUBLICATIONS INCLUDED IN THIS THESIS... 9 CONTRIBUTIONS BY OTHERS TO THE THESIS STATEMENT OF PARTS OF THE THESIS SUBMITTED TO QUALIFY FOR THE AWARD OF ANOTHER DEGREE ACKNOWLEDGEMENTS KEYWORDS AUSTRALIAN AND NEW ZEALAND STANDARD RESEARCH CLASSIFICATIONS (ANZSRC) FIELDS OF RESEARCH (FOR) CLASSIFICATION LIST OF FIGURES LIST OF TABLES LIST OF ABBREVIATIONS USED CHAPTER INTRODUCTION THESIS AIMS AND HYPOTHESES Aims of the Research Thesis Hypotheses CHAPTER THE PROBLEM OF WHIPLASH THE MECHANISM OF INJURY POSSIBLE PATHOANATOMICAL LESIONS FOLLOWING MOTOR VEHICLE COLLISIONS Pathoanatomical Lesions and Imaging

21 2.3.2 Pathoanatomical Lesions and Clinical Findings PATHOPHYSIOLOGICAL PROCESSES FOLLOWING INJURY MEASUREMENT OF PAIN PROCESSES IN CHRONIC WAD Summary of Changes in Pain Processing Mechanisms NEUROMUSCULAR AND MOVEMENT DYSFUNCTION IN THE PRESENCE OF NECK PAIN Clinical Findings in WAD Morphological Changes Changes in Motor Control Movement Dysfunction Sensorimotor Dysfunction Summary PSYCHOLOGICAL FEATURES IN WAD CHAPTER INTRODUCTORY REMARKS THE FACET JOINT AS A SOURCE OF NOCICEPTION IN WAD Basic Science Experiments Clinical Diagnosis of Facet Joint Pain THE NEED FOR AN EFFECTIVE TREATMENT SOLUTION FOR CHRONIC WAD Conservative Treatment Efficacy Efficacy of RadioFrequency Neurotomy (RFN) Other Considerations Sensory Features Movement and Motor Control Dysfunction Psychological Features CONCLUSIONS CHAPTER STUDY Abstract Introduction Methods Procedures Data Analysis Results Participants Physical Measures

22 4.1.9 Psychological Measures Discussion Conclusion CHAPTER STUDY Abstract Introduction Methods Data Analysis Results Participants Pain and Disability Pressure Pain Thresholds (PPT) Nociceptive Flexion Reflex (NFR) Brachial Plexus Pain Provocation Test (BPPT) Cold Pain Thresholds (CPT) Heat Pain Thresholds (HPT) Range of Motion (ROM) Cranio-cervical Flexion Test (CCFT) Discussion Conclusions STUDY Abstract Introduction Materials and Methods Data Analysis Results Participants General Health Questionnaire (GHQ-28) Pain Catastrophization (PCS) Posttraumatic Stress (PDS) Discussion CHAPTER STUDY Abstract

23 6.1.2 Introduction Materials and Methods Data Analysis Results Participants Disability Questionnaires Physical Measures Discussion CHAPTER STUDY Abstract Introduction Materials and Methods Data Analysis Results Discussion CHAPTER OVERVIEW DETERMINATION OF CLINICAL FEATURES OF INDIVIDUALS WITH CERVICAL FACET MEDIATED PAIN PHYSICAL MANIFESTATIONS OF CHRONIC WAD ARE MODULATED BY CERVICAL RFN PSYCHOLOGICAL MANIFESTATIONS OF CHRONIC WAD ARE MODULATED BY CERVICAL RFN PHYSICAL AND PSYCHOLOGICAL MANIFESTATIONS DETERIORATE ON RETURN OF PAIN LOW DISABILITY OR LOW PAIN CATATASTROPHIZATION PREDICTS SUCCESS OF CERVICAL RFN OVERALL SIGNIFICANCE OF FINDINGS IMPLICATIONS OF RESEARCH LIMITATIONS OF RESEARCH FUTURE RESEARCH OTHER RESEARCH CONSIDERATIONS CONCLUSION REFERENCES:

24 APPENDIX 1: INSTRUMENTATION QUANTITATIVE SENSORY TESTS: MOTOR MEASURES: QUESTIONNAIRES: APPENDIX 2: RFN PROCEDURE APPENDIX 3: ETHICAL CLEARANCE HEALTHY CONTROLS CONSENT FORM HEALTHY CONTROL DEMOGRAPHICS WHIPLASH GROUP (WAD_R OR WAD_NR) CONSENT FORM WHIPLASH GROUP (WAD_R OR WAD_NR) DEMOGRAPHICS MOTOR VEHICLE COLLISION DESCRIPTION APPENDIX 4: QUESTIONNAIRES VISUAL ANALOGUE SCALE (VAS) NECK DISABILITY INDEX ITEM GENERAL HEALTH QUESTIONNAIRE POST TRAUMATIC DIAGNOSTIC SCALE PAIN CATASTROPHIZING SCALE S-LANSS POST-RFN QUESTIONNAIRE APPENDIX 5: RESULTS A. STUDY 1: BETWEEN GROUP COMPARISON (HEALTHY CONTROLS, WAD_NON RESPONDERS & WAD_RESPONDERS A1: VISUAL ANALOGUE SCALE (VAS) VS. GROUP INDEPENDENT T-TEST ANALYSIS A2: NECK DISABILITY INDEX (NDI) VS. GROUP INDEPENDENT T-TEST ANALYSIS A3: PAIN OF PREDOMINANTLY NEUROPATHIC ORIGIN (S-LANSS) VS. GROUP MANN-WHITNEY U ANALYSIS A3.1: PROPORTION OF INDIVIDUALS WITH ELEVATED S-LANSS ( 12) SCORES VS. GROUP CHI- SQUARED ANALYSIS A4: PRESSURE PAIN THRESHOLDS (PPT): CERVICAL SPINE, MEDIAN NERVE AND TIBIALIS ANTERIOR SITES (LOG TRANSFORMED DATA) VS. GROUP MANOVA ANALYSIS A4.1: PPT POST HOC ANALYSIS MANOVA TEST MATRIX: HC VS. WHIPLASH GROUPS

25 A4.2: PPT POST HOC ANALYSIS MANOVA TEST MATRIX: WAD_R VS. WAD_NR A5: COLD PAIN THRESHOLDS (CPT) VS. GROUP KRUSKAL-WALLIS ANALYSIS A6: HEAT PAIN THRESHOLDS (HPT) VS. GROUP KRUSKAL-WALLIS ANALYSIS A7: BRACHIAL PLEXUS PROVOCATION TEST (BPPT) ELBOW EXTENSION RANGE OF MOTION (ROM) VS. GROUP ONE-WAY ANOVA ANALYSIS OF LOG TRANSFORMED DATA A8: NOCICEPTIVE FLEXION REFLEX (NFR) VS. GROUP ONE-WAY ANOVA ANALYSIS OF LOG TRANSFORMED DATA A8.1 POST HOC ANALYSIS NFR THRESHOLD A9.1: POST HOC ANALYSIS ROM MANOVA TEST MATRIX: HC VS. WHIPLASH GROUP S A9.2: POST HOC ANALYSIS ROM - MANOVA TEST MATRIX: WAD_R VS. WAD_NR A10: EMG OF THE SUPERFICIAL NECK MUSCULATURE (22MMHG, 24MMHG, 26MMHG, 28MMHG AND 30MMHG) VS. GROUP MANOVA ANALYSIS A10.1: POST HOC ANALYSIS: EMG MANOVA TEST MATRIX: HC VS. WHIPLASH GROUP S A10.2: POST HOC ANALYSIS: EMG MANOVA TEST MATRIX: WAD_R VS. WAD_NR A11: PSYCHOLOGICAL DISTRESS (GHQ-28) VS. GROUP KRUSKAL-WALLIS ANALYSIS A11.1: PROPORTION OF INDIVIDUALS WITH PSYCHOLOGICAL DISTRESS (GHQ-28) VS. GROUP CHI- SQUARED ANALYSIS A12: PAIN CATASTROPHIZATION (PCS) VS. GROUP (WAD_NR & WAD_R) MANN-WHITNEY U ANALYSIS A12.1: PROPORTION OF INDIVIDUALS IN THE TWO WHIPLASH GROUPS (WAD_NR & WAD_R) WITH ELEVATED ( 30) PCS SCORES CHI-SQUARED ANALYSIS A13: PROPORTION OF INDIVIDUALS IN THE TWO WHIPLASH GROUPS (WAD_NR & WAD_R) THAT FULFILL THE PTSD CRITERIA (UTILIZING THE PDS SCALE) CHI-SQUARED ANALYSIS A13.1: POST TRAUMATIC STRESS SEVERITY (PDS) SCORES VS. GROUP (WAD_NR & WAD_R) MANN- WHITNEY U ANALYSIS B. STUDY 2: PARTICIPANTS UNDERGOING RADIOFREQUENCY NEUROTOMY LONGITUDINAL ANALYSIS OF PHYSICAL MEASURES B1: VAS VS. TIME REPEATED MEASURES ANOVA ANALYSIS B1.1: POST-HOC ANALYSIS: VAS VS. TIME B2: NDI VS. TIME REPEATED MEASURES ANOVA ANALYSIS B2.1: POST-HOC ANALYSIS: NDI VS. TIME B3: LOG CERVICAL SPINE PPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS B3.1: POST-HOC ANALYSIS: LOG CERVICAL SPINE PPT VS. TIME B3.2: LOG CERVICAL SPINE PPT VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B3.3: LOG CERVICAL SPINE PPT VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B4: LOG MEDIAN NERVE PPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS

26 B4.1: POST-HOC ANALYSIS: LOG MEDIAN NERVE PPT VS. TIME B4.2: LOG MEDIAN NERVE PPT VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B4.3: LOG MEDIAN NERVE PPT VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B5: LOG TIBIALIS ANTERIOR PPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS B5.1: POST-HOC ANALYSIS: LOG TIBIALIS ANTERIOR PPT VS. TIME B5.2: LOG TIBIALIS ANTERIOR PPT VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B5.3: LOG TIBIALIS ANTERIOR PPT VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B6: LOG NOCICEPTIVE FLEXION REFLEX THRESHOLD (NFR) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B6.1: POST-HOC ANALYSIS: LOG NFR VS. TIME B6.2: LOG NFR VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B6.3: LOG NFR VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B7: LOG BRACHIAL PLEXUS PROVOCATION TEST (BPPT) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B7.1: POST-HOC ANALYSIS: LOG BPPT VS. TIME B7.2: LOG BPPT VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B7.3: LOG BPPT VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B8: COLD PAIN THRESHOLD (CPT) VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS B8.2: CPT VS. GROUP (T(2): PRIOR TO RFN) MANN WHITNEY U TEST B8.3: CPT VS. GROUP (T(4): POST-RFN) MANN WHITNEY U TEST B9: HEAT PAIN THRESHOLD (HPT) VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS B9.2: HPT VS. GROUP (T(2): PRIOR TO RFN) MANN WHITNEY U TEST B9.3: HPT VS. GROUP (T(4): POST-RFN) MANN WHITNEY U TEST B10: RANGE OF MOTION (ROM) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B10.1: POST-HOC ANALYSIS: ROM VS. TIME B10.2: ROM VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B10.3: ROM VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B11: CRANIO-CERVICAL EMG (22MMHG) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B11.1: EMG (22MMHG) VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B11.2: EMG (22MMHG) VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B12: CRANIO-CERVICAL EMG (24 MMHG) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B12.1: POST-HOC ANALYSIS: 24MMHG EMG VS. TIME B12.2: EMG (24MMHG) VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B12.3: EMG (24MMHG) VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B13: CRANIO-CERVICAL EMG (26 MMHG) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B13.1: POST-HOC ANALYSIS: 26MMHG EMG VS. TIME B13.2: EMG (26MMHG) VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST

27 B13.3: EMG (26MMHG) VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B14: CRANIO-CERVICAL EMG (28 MMHG) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B14.1: POST-HOC ANALYSIS: 28MMHG EMG VS. TIME B14.2: EMG (28MMHG) VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B14.3: EMG (28MMHG) VS. GROUP (T(4): POST-RFN) INDEPENDENT T-TEST B15: CRANIO-CERVICAL EMG (30 MMHG) VS. TIME REPEATED MEASURES ANOVA ANALYSIS B15.1: EMG (30MMHG) VS. GROUP (T(2): PRIOR TO RFN) INDEPENDENT T-TEST B15.2: EMG (30MMHG) VS. GROUP (T(2): POST-RFN) INDEPENDENT T-TEST C. STUDY 3: PARTICIPANTS UNDERGOING RADIOFREQUENCY NEUROTOMY LONGITUDINAL ANALYSIS OF PSYCHOLOGICAL MEASURES C1: GHQ-28 VS. TIME CHI-SQUARED ANALYSIS C1.1: GHQ-28 VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C2.1: GHQ-28 (SOMATIC SUBSCALE) VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C3.1: GHQ-28 (ANXIETY/SLEEPLESSNESS SUBSCALE) VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C4.1: GHQ-28 (SOCIAL DYSFUNCTION SUBSCALE) VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C5.1: GHQ-28 (SEVERE DEPRESSION SUBSCALE) VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C5.2: PCS VS. TIME CHI-SQUARED ANALYSIS C6.1: PCS VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C7: PDS (FULFILLING PTSD CRITERIA) VS. TIME CHI-SQUARED ANALYSIS C7.1: PDS SEVERITY SCORE VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS C7.2: PDS SYMPTOM SCORE VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS D. STUDY 4: RETURN OF PAIN LONGITUDINAL ANALYSES D1: NDI VS. TIME REPEATED MEASURES ANOVA ANALYSIS D1.1: POST-HOC ANALYSIS: NDI VS. TIME D2: LOG CERVICAL SPINE PPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS D2.1: POST-HOC ANALYSIS: LOG CERVICAL SPINE PPT VS. TIME D3: LOG MEDIAN NERVE PPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS D3.1: POST-HOC ANALYSIS: LOG MEDIAN NERVE PPT VS. TIME D4: LOG TIBIALIS ANTERIOR PPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS D4.1: POST-HOC ANALYSIS: LOG TIBIALIS ANTERIOR PPT VS. TIME D5: LOG NFR VS. TIME REPEATED MEASURES ANOVA ANALYSIS D5.1: POST-HOC ANALYSIS: LOG NFR VS. TIME

28 D6: LOG BPPT VS. TIME REPEATED MEASURES ANOVA ANALYSIS D6.1: POST-HOC ANALYSIS: LOG BPPT VS. TIME D7: CPT VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D7.1: POST-HOC ANALYSIS: CPT VS. TIME D8: HPT VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D8.1: POST-HOC ANALYSIS: HPT VS. TIME D9: ROM VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D9.1: POST-HOC ANALYSIS: ROM VS. TIME D10: EMG (22MMHG) VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D10.1: POST-HOC ANALYSIS: EMG (22MMHG) VS. TIME D11: EMG (24MMHG) VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D12: EMG (26MMHG) VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D12.1: POST-HOC ANALYSIS: EMG (26MMHG) VS. TIME D13: EMG (28MMHG) VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D13.1: POST-HOC ANALYSIS: EMG (28MMHG) VS. TIME D14: EMG (30MMHG) VS. TIME ONE-WAY REPEATED MEASURES ANOVA ANALYSIS D15: GHQ-28 VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS D16: PCS VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS D17: PDS (FULFILLING PTSD CRITERIA) VS. TIME CHI-SQUARED ANALYSIS D17.2: PDS SYMPTOM SCORE VS. TIME REPEATED MEASURES FRIEDMAN ANALYSIS E: STUDY 5: PREDICTORS OF CERVICAL RADIOFREQUENCY NEUROTOMY SUCCESS E1.1: PROPORTION OF INDIVIDUALS BY GENDER IN THE TWO WHIPLASH GROUPS (SUCCESS AND LESS SUCCESSFUL) CHI-SQUARED ANALYSIS E1.2: AGE VS. GROUP (SUCCESS AND LESS SUCCESSFUL) INDEPENDENT T-TEST E1.3: DURATION OF SYMPTOMS VS. GROUP (SUCCESS AND LESS SUCCESSFUL) MANN WHITNEY U ANALYSIS E1.4: PAIN VS. GROUP (SUCCESS AND LESS SUCCESSFUL) INDEPENDENT T-TEST E1.5: DISABILITY VS. GROUP (SUCCESS AND LESS SUCCESSFUL) INDEPENDENT T-TEST E1.6: LOGPPTC VS. GROUP (SUCCESS AND LESS SUCCESSFUL) INDEPENDENT T-TEST E1.7: LOGPPTTIBANT VS. GROUP (SUCCESS AND LESS SUCCESSFUL) INDEPENDENT T-TEST E1.8: COLD VS. GROUP (SUCCESS AND LESS SUCCESSFUL) INDEPENDENT T-TEST E1.9: PAIN CATASTROPHIZATION (PCS) VS. GROUP (SUCCESS AND LESS SUCCESSFUL) MANN-WHITNEY U ANALYSIS E1.10: POST TRAUMATIC STRESS SEVERITY (PDS) VS. GROUP (SUCCESS AND LESS SUCCESSFUL) MANN- WHITNEY U ANALYSIS E2.1: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = PAIN

29 E2.2: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = DISABILITY E2.3: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = PAIN CATASTROPHIZATION E2.4: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = LOGPPTCERVICAL E2.5: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = LOGPPTTIBANT E2.6: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = COLD E2.7: UNIVARIATE LOGISTIC REGRESSION: PREDICTOR VARIABLE = POST TRAUMATIC STRESS SEVERITY E3: CORRELATIONS BETWEEN PREDICTOR VARIABLES E4.1: STEPWISE MULTIVARIABLE LOGISTIC REGRESSION: PREDICTOR VARIABLE = DISABILITY E4.2: STEPWISE MULTIVARIABLE LOGISTIC REGRESSION: PREDICTOR VARIABLE = PAIN CATASTROPHIZATION E5.1: DIAGNOSTIC ACCURACY IN PREDICTING SUCCESS FOR PREDICTOR VARIABLE = PAIN CATASTROPHIZATION (PCS) E5.2: ROC CURVE FOR PREDICTOR VARIABLE = PCS E5.3: DIAGNOSTIC ACCURACY IN PREDICTING SUCCESS FOR PREDICTOR VARIABLE = DISABILITY E5.4: ROC CURVE FOR PREDICTOR VARIABLE = DISABILITY

30 List of Figures Figure 2.1: Figure 2.2: Figure 2.3: Figure 4.1: Figure 4.2: Figure 4.3: Figure 6.1: Figure 6.2: Figure 6.3: Figure 6.4: S-shaped cervical spine curve occurring approximately ms following rear impact. Based on BodyMind Publications, 2002; reprinted with permission. The development of motion resulting in the S-shaped cervical spine curve and supposed injury mechanism. Based on BodyMind Publications, 2002; reprinted with permission. The C shaped aspect of the cervical spine occurring at approximately ms of the whiplash event. Based on BodyMind Publications, 2002; reprinted with permission. Flow of participants through study 1 (WAD_R & WAD_NR) Comparison of cervical ROM between groups (WAD_R; WAD_NR & HC) Cranio-cervical flexion test performance across groups (WAD_R; WAD_NR & HC) Thermal pain thresholds (means and SEM) over time in the WAD participants who underwent RFN (n=53) Pressure pain thresholds (means and SEM) over time in the WAD participants who underwent RFN (n=53) Total (Flexion, Extension and Rotation) ROM (means and SE) over time in the WAD participants who underwent RFN (n=53) Cranio-Cervical Flexion Test RMS values (medians) over time in the WAD participants who underwent RFN (n=53)

31 List of Tables Table 4.1 Table 4.2 Table 4.3 Table 4.4 Table 4.5 Table 5.1 Table 5.2 Table 5.3: Table 5.4: Table 5.5: Table 5.6: Table 6.1: Table 7.1: Table 7.2: Table 7.3: Table 7.4: The prevalence of cervical joints injected in the whiplash cohort (n=90) Medication use at intake of each participant (WAD_R & WAD_NR) The demographic characteristics of participant groups (WAD_R; WAD_NR & HC) Median [Interquartile Range] scores and p values for sensory measures (WAD_R & WAD_NR) Median [Interquartile Range] scores of each group for psychological measures (WAD_R; WAD_NR and HC) Demographics of participants and changes in pain and disability over time in the WAD participants who underwent RFN (n=53) Summary of sensory measures over the four time points in the WAD participants who underwent RFN (n=53) Summary of thermal pain thresholds over time in WAD participants undergoing RFN (n=53) vs. healthy controls (n=30) CCFT RMS values (medians [IQR]) over time for WAD participants undergoing RFN (n=53) vs. healthy controls (n=30) Median [Interquartile Range] scores for psychological measures over time for WAD participants undergoing RFN (n=53) Median [Interquartile Range] scores for each sub-component of the GHQ- 28 for WAD participants undergoing RFN (n=53) Disability and Psychological Scores over time in the WAD participants who underwent RFN (n=53) Patient Characteristics by Group (Success vs. Less Successful RFN Outcome) Status Prior to cervical RFN Group differences (Success vs. Less Successful RFN Outcome) vs. time prior to and following cervical radiofrequency neurotomy (RFN) Correlations between clinical outcome measures prior to cervical RFN Accuracy statistics with 95% confidence intervals for the two models (NDI and PCS) predicting success of cervical RFN at 3 months

32 List of Abbreviations Used BPPT: Brachial plexus provocation test CCFT: Cranio-cervical flexion test CNS: Central Nervous System CPM: Conditioned Pain Modulation CPT: Cold pain threshold EMG: Electromyography FB: Facet blocks GHQ-28: General Health Questionnaire-28 GROC: Global Rating of Change HC: Healthy controls HPT: Heat pain threshold IAB: Intra-articular block IES: Impact of Events Scale IQR: Interquartile range JPE: Joint position error LSD: Least significant difference M(ANOVA): Multivariate (analysis of variance) MBB: Medial branch block MDC: Minimal detectable change MRI: Magnetic resonance imaging MVC: Motor vehicle collision NDI: Neck Disability Index NFR: Nociceptive flexion reflex PCS: Pain Catastrophizing Scale PDS: Posttraumatic stress Diagnostic Scale PFActS-C: Pictorial Fear of Activity Scale - Cervical PPT: Pressure pain threshold PTSD: Posttraumatic stress disorder QST: Quantitative Sensory Testing QTF: Quebec Task Force

33 RCT: Randomized Controlled Trial RFN: Radiofrequency neurotomy RMS: Root mean squared ROM: Cervical range of movement SCM: Sternocleidomastoid SD: Standard Deviation s-lanss: Self report Leeds Assessment of Neuropathic Symptoms and Signs SMD: Significant Mean Difference SP: Substance P SPNTT: Smooth Pursuit Neck Torsion Test TSK: TAMPA Scale of Kinesphobia t(1): time period following cervical facet joint blockade upon return of pain t(2): time period immediately prior to receiving radiofrequency neurotomy t(3): time period one-month following radiofrequency neurotomy t(4): time period three-months following radiofrequency neurotomy t(5): time period following return of pain after effects of RFN have abated t1: time period prior to receiving RFN (mean of t(1) and t(2)) t2: time period following RFN (mean of t(3) and t(4)) t3: time period following return of pain after effects of RFN have abated (=t(5)) TPT: Thermal pain threshold VAS: Visual Analogue Scale WAD: Whiplash associated disorders WAD_NR: WAD non-responders WAD_R: WAD responders WAD_RF: WAD individuals who proceeded to and underwent radiofrequency neurotomy

34 CHAPTER Introduction Whiplash injury following a motor vehicle collision (MVC) was first described by Crowe in 1928 [1]. Whiplash associated disorders (WAD) were subsequently defined to accommodate the variety of symptoms that are reported following a whiplash injury [2]. Unfortunately, individuals do not always recover from whiplash injury, with recent systematic reviews concluding that approximately 50% of whiplash injured individuals continue to reveal symptoms 12 months following the initial event [3-8]. Thus, WAD is costly, both for the individual and society in general [2], with a significant proportion of medical costs associated with management of individuals who develop chronic pain and disability [9]. The heterogeneous nature of WAD makes treatment of these individuals challenging. Although the predominant symptom is neck pain, individuals can present with a variety of symptoms (e.g. headaches, dizziness, visual and auditory disturbances, temporo-mandibular joint pain, photophobia, fatigue, cognitive difficulties such as concentration and memory loss, anxiety, depression and insomnia amongst others) [10-13]. It is challenging to determine the underlying cause of these symptoms. It is unknown if these symptoms stem from discrete pathoanatomical lesions; as current diagnostic imaging techniques fail to identify a specific pathoanatomical lesion in the majority of patients. Although anatomical lesions have been implicated from biomechanical [14-21], autopsy [22-25] and clinical studies [26-28], some authors question the credibility of patients subjective symptoms and question whether factors such as exaggeration (or even secondary gain) may be responsible for ongoing symptom presentation [29]. Despite this cynicism, recent research has identified several factors that may contribute to chronic symptoms in individuals with WAD, more specifically, various altered sensory, motor and psychological manifestations [30]. In regard to sensory features, clinical studies (generally involving psychophysical tests investigating the relationship between physical stimuli and pain) have demonstrated the presence of both local and widespread sensory hypersensitivity to a variety of stimuli, including induced experimental pain [31], electro-cutaneous stimulation [32] and mechanical stimulation

35 [33,34], which are suggestive of altered central nervous system (CNS) processing [35]. Aberrant CNS processing manifesting as pain hypersensitivity has been described as being indicative of central sensitization or central hyperexcitability [36]. Reduced active cervical range of motion (ROM); altered muscle recruitment patterns in the upper quadrant and morphological changes in the neck extensor and flexor muscles [37-44] have also been demonstrated; whilst aberrant sensori-motor features include an inability to accurately relocate the head in space, balance deficits and disturbed ocular movement control [13,45-47]. Further to these physical features, psychological manifestations have also been identified [48-50]; generally in those with poor recovery and ongoing pain and disability [51,52], and these features could also contribute to the persistence of symptoms. The mechanisms underlying the persistence of these factors in those with chronic WAD are not clear. There is much debate as to whether these manifestations are driven by an ongoing peripheral nociceptive source (the anatomical lesion) [53-55] or are self-maintaining due to neuroplastic changes in the central nervous system [56]. The determination of an anatomic source of nociception is required to explore the proposal that the various symptomatic manifestations of chronic WAD are driven by an ongoing peripheral nociceptive source, (such as a lesion to a cervical facet joint). Current diagnostic imaging usually fails to identify an accurate pathoanatomical diagnosis in individuals with WAD, but diagnostic criteria have been established for cervical facet joint dysfunction using alternate diagnostic methods [57]. Comparative medial branch blocks (MBB) are one such alternative, demonstrating face validity, construct validity and criterion validity for the diagnosis of neck pain arising from the cervical facet joint [58,59]. Using placebo controlled MBB, one study estimated that the prevalence of cervical facet-mediated pain in individuals with persistent neck pain following whiplash trauma was approximately 60% [28], whilst in another study using controlled doubleblind anaesthetic blocks, prevalence was estimated to be approximately 75% [60]. It must be noted that these studies involved small sample sizes, and the participants in the studies were highly selected subsets of the overall whiplash-injured population. However, an effective treatment for patients who respond to cervical MBB is available, namely radiofrequency neurotomy (RFN), which has been demonstrated to provide long

36 lasting pain relief (between 7-14 months) for those individuals previously responding to comparative cervical MBB [61]. The model of facet joint lesions, diagnosis with MBB and alleviation of symptoms with RFN allows research into the question of whether the persistence of nociception arising from injured structures is responsible for the variety of sensory, motor and psychological symptoms demonstrated in individuals with chronic WAD [30], and whether these features can be modulated by reducing peripheral nociception through successful RFN. This will allow clinicians information to assist with management of patients with these clinical features. 1.2 Thesis Aims and Hypotheses This research program investigated the effects of modulation of cervical facet joint nociception on sensory, motor and psychological features identified in patients with chronic WAD [62]. Reliable and validated outcome measures of sensory, motor function and psychological distress as used in previous research of chronic WAD [34,35,63-68] were used in a pre-post test, prospective cohort design involving individuals with chronic WAD and healthy control participants to investigate these relationships further Aims of the Research The overall purpose of this thesis was to determine if there was modulation of central nervous system hyperexcitability, motor function and psychological distress in individuals with chronic WAD grade II (patient complaint of neck pain with presence of musculoskeletal signs including decreased ROM and point tenderness [2]) following RFN to the cervical spine. The specific aims of the research were: 1) To determine differences in the physical and psychological manifestations of individuals with chronic WAD who respond to MBBs compared to those who do not respond and healthy controls; 2) To determine if there was attenuation of psychophysical indicators of central hyperexcitability, improvements in motor function and psychological manifestations in individuals with chronic WAD following RFN to the cervical spine;

37 3) To determine if changes in central hyperexcitability, motor function and psychological distress reverted when pain returns post-rfn; 4) To determine which clinical factors predict a successful response to cervical RFN Thesis Hypotheses The hypotheses for these studies were: 1) Individuals with chronic WAD who do not respond to facet blocks will demonstrate greater levels of central hyperexcitability, poorer motor function and increased psychological distress compared to responders to facet blocks. Both groups will demonstrate greater impairments in these measures compared to a healthy cohort; 2) There will be significant improvements in psychophysical indicators of central hyperexcitability, motor function and psychological distress following RFN; 3) There will be a significant deterioration of psychophysical indicators of central hyperexcitability, motor function and psychological distress when pain eventually returns when the effects of RFN abate; 4) Higher levels of pain, disability, sensory hypersensitivity, psychological distress and pain catastrophization will be associated with poor response to RFN

38 CHAPTER 2 Sensory, Motor and Psychological Features of Chronic Whiplash Associated Disorders. This chapter presents an overview of whiplash including features related to the pathomechanics of injury, the pathoanatomical and pathophysiological mechanisms of WAD and the impairments that characterize the chronic condition. As the body of work in this thesis concentrates on the modulation of features evident in chronic WAD, this chapter provides the background and basis for understanding the development of these clinical features. 2.1 The Problem of Whiplash Whiplash can be defined as an acceleration deceleration mechanism of energy transfer to the neck, usually as a result of a motor vehicle collision (MVC). The impact may result in bony or soft-tissue injuries (whiplash injury), which in turn may lead to a variety of clinical manifestations (Whiplash Associated Disorders - WAD) [2]. Neck pain is the primary symptom, but other symptoms such as headaches, dizziness, memory and concentration difficulties are also reported [69]. As a result, some authors describe the consequences of chronic WAD as being like those of a systemic illness or chronic pain syndrome [70,71]. Cumulative incidence rates for whiplash injury vary between countries and reporting procedures, with recent studies reporting a range from 114 (Victoria, Australia) to 300 (Saskatchewan, Canada) per 100,000 inhabitants [72-75]. Individuals still symptomatic six months or more after the injury, are designated as chronic by the Quebec Task Force [2]. Recently, the Bone and Joint Task Force on neck pain and its associated disorders, in a best evidence synthesis of the literature, reported that approximately half of those with WAD report symptoms one year after their injury [3]. Other studies have reported various chronicity rates; ranging from 15-84% [2,76-78]. This compares to the background prevalence of neck pain in the general population of between 40-50%, although the same best-evidence synthesis noted that the prevalence of activity-limiting pain was between 2-12% [79]

39 Much of the medical cost associated with WAD can be attributed to the management of those patients with chronic symptoms [80], with one study revealing that 12% of patients with chronic whiplash pain account for 47% of the costs [9]. In 2007, the Insurance Bureau of Canada (IBC) reported that whiplash injuries account for 2 million insurance claims each year at a cost of approximately $8.5 billion [81]. The annual societal costs in the United States approach $231 billion annually [82], whilst in the UK it is estimated that 3 billion is spent annually on claims [83]. The societal costs in the United States include medical and ancillary costs, property damage; loss of wages, workplace disruption, legal fees, vocational rehabilitation, emergency services, administrative fees, traffic congestion caused by accidents, and lost quality of life [82]. Thus, approaches that help prevent and effectively treat pain arising from WAD would assist in easing the financial and social burden on the individual and society in general. 2.2 The Mechanism of Injury It is generally considered that acute whiplash symptoms are as a result of injuries to cervical structures being sustained in the MVC [84-87]. Such anatomical lesions may also explain the presence of non-resolved chronic pain [28]. However, since a pathoanatomical diagnosis for whiplash pain cannot usually be made, it has been proposed that other factors such as psychological ones or factors associated with the compensation process may be the drivers of a chronic condition [29,83]. Support for an anatomical basis for ongoing symptomatology arises from epidemiological studies evaluating injury rates following changes in motor vehicle seat design, which were associated with a 43% reduction in reported neck injury rates [88]. The changes in car seat design were developed in response to the study of the biomechanical forces being transmitted to the neck during a MVC. The biomechanics of the human spine in a rear-end MVC have been studied extensively, through cadaveric observations, human volunteer collision tests and finite analysis modeling [15,17,18,89-91]. The kinematics of the spine as it is subjected to this vector is described consistently in a number of studies [15,17,18,89]. In the rear end collision, an S-shaped curvature within the cervical spine has been described [15,89,92,93]. This results in the upper cervical spine moving into relative flexion and the lower cervical

40 spine into extension (Fig. 2.1). In this vector of collision at impact, the car seat begins to move forward, whilst the occupant remains stationary due to inertia. Upper cervical flexion Lower cervical extension Figure 2.1: S-shaped cervical spine curve occurring approximately ms following rear impact Based on BodyMind Publications, 2002; reprinted with permission. At approximately 50milliseconds (ms), the car seatback ramps the torso upward and forward moving the spine forward with concurrent cervical spine posterior rotation, resulting in a straightening of the lumbar, thoracic and cervical spines. This adds further compressive forces to the cervical spine [94] (Fig. 2.2). a b Figure 2.2: The development of motion resulting in the S-shaped cervical spine curve and supposed injury mechanism. Based on BodyMind Publications, 2002; reprinted with permission

41 At approximately ms, as the car seat pushes into the occupant s torso, the torso is accelerated forward of the lower cervical spine, thus resulting in extension (C-shape) of the head and lower cervical spine as the centre of gravity results in the head lowering [93,94] (Fig. 2.3). By 160ms, the torso is fully accelerated by the car seat, thus causing the lower neck to be pulled forward by the rapidly moving torso [94]. After ms, the head and torso are accelerated forward ahead of the car seat, resulting in flexion of the spine [94]. By approximately 600 ms the occupant has returned to the initial position [94]. Unfortunately; the reflexive muscle actions that may restrain this action are unable to do so as a result of the latencies associated with initiation of muscular contraction being longer than the duration of this event [93]. Figure 2.3: The C shaped aspect of the cervical spine occurring at approximately ms of the whiplash event. Based on BodyMind Publications, 2002; reprinted with permission. This non-physiological S-shaped motion is thought to be responsible for the injuries observed, as at no time does the cervical spine as a whole exceed its physiological motion [89,90]. However, the lower cervical spine has been shown to exceed its physiological posterior rotation range of motion (ROM) [90,94]. It is proposed that this mechanism results in synovial fold impingement [15]. This motion also results in increased tension in the

42 anterior vertebral structures (e.g. disc, anterior longitudinal ligament), facet joint capsular ligaments and synovial membrane [19,20,23,24,95-98]. Replicating this mechanism of injury, simulated whiplash acceleration trauma models have revealed peak facet joint compression at C4/5 with maximum capsular ligament strains occurring at C6/7 [18]. Recently, similar studies have been performed to describe the segmental kinematics of the cervical spine utilising the side impact vector of collision [99,100]. Proposed segmental kinematics have also been described for frontal collision vectors [101,102], confirming that these mechanisms of injury also demonstrate the potential to result in cervical spine injury. 2.3 Possible Pathoanatomical Lesions Following Motor Vehicle Collisions Evidence for a pathoanatomical lesion following a whiplash injury comes from several sources. Taylor and Twomey performed studies on road trauma victims, who died from causes other than spinal injuries [23,24]. The cervical spines were subjected to radiographic and magnetic resonance imaging (MRI) scanning prior to autopsy. They were then resectioned and examined microscopically. The autopsy results were compared to those of the imaging. It was found that imaging often did not reveal a variety of injuries in and around the cervical bone and soft tissue structures. Autopsy findings included bleeding into the facet joints, bleeding in and around the nerve root and dorsal root ganglion, tearing of the discs at the rim attachments and vertebral bodies, tearing and bruising of the ligaments of the spine, as well as tearing and bleeding into the muscles. They also noted occasional bruising of the spinal cord [24]. Other dissection studies have revealed similar findings [22,25]. Furthermore, studies utilising high speed cinematography in healthy controls and cadavers [15], animal studies [103,104] and cryomicroscopy [105] provide evidence that injuries to the majority of cervical spine structures including the disc, dorsal root ganglion, ligamentous tissue, nervous tissue, vertebral artery and neck muscles are possible [97,98,103,104, ]. Thus, injuries to various cervical neuromusculoskeletal tissues have been demonstrated via autopsy and in a variety of basic science and human experimental settings Pathoanatomical Lesions and Imaging Despite advances in imaging technology (primarily MRI), imaging the neck for whiplash injuries (excluding fractures) usually fails to reveal any significant pathology [25,114]. Conventional imaging is likely not sensitive enough to reveal possible

43 pathoanatomical lesions in WAD grades I-III [23,24,105,115]. Even when lesions are identified, their clinical significance has been debated. A recent example was MRI findings demonstrating possible tears of the craniovertebral ligaments [ ]. Similar pathologic changes were subsequently observed in these ligaments in asymptomatic, aged individuals and individuals with insidious onset neck pain [ ]. Moreover, even when these changes were detected by MRI, correlation with clinical symptoms of WAD was questionable [124] Pathoanatomical Lesions and Clinical Findings As diagnostic imaging is largely unhelpful, there is a necessary reliance on other clinical findings to guide decision making regarding diagnosis and patient care. There is considerable similarity in symptoms from various musculoskeletal pathologies in the neck region. Pain mapping reveals considerable overlap in areas of symptoms from cervical disc pathology [125], cervical facet-joints [126], nerve root pathology [127] or muscle [31]. Physical examination also fails to identify distinct pathoanatomical findings with any greater clarity than self-report of symptoms [128]. The close anatomical relationship of cervical structures indicates the possibility of multiple lesions following whiplash trauma (e.g. cervical disc and facet joint pathology) [27] to further confound the clinical picture. As it is difficult to accurately locate specific pathoanatomical lesions, it is unknown what role these lesions have in an individual s clinical presentation. Attention has therefore diverted to the mechanisms and impairments underlying clinical symptoms. Many advocate that a treatment approach directed towards subgrouping individuals with consistent underlying impairments [129,130], or successful treatment of the mechanisms and processes underlying impairments of painful musculoskeletal conditions may improve outcomes [131]. This would allow the manifestations of any underlying pathology to be treated appropriately, no matter where the lesion exists. 2.4 Pathophysiological Processes Following Injury Augmented central nervous system (CNS) nociceptive processes (or central hyperexcitability) can explain many features of persistent pain hypersensitivity after peripheral tissue injury [132]. Central hyperexcitability has been defined as changes in the

44 CNS that occur after injury which are responsible for enhanced neuronal excitability and pain perception [54] and is induced by peripheral nociceptive stimulation [133]. It has been described as a possible mechanism for the persistence of pain [54]. The presence of central hyperexcitability is one of the factors that may explain the discrepancy between the apparent lack of tissue damage and the magnitude of pain complaints in individuals with WAD. Clinical identification of central hyperexcitability [134] may assist in screening patients for specific treatment approaches (such as appropriate education and medication) in an attempt to improve outcomes [35,135]. The development of central hyperexcitability is generally thought to arise from the initial injury [36] and inflammatory response (marked by release of potassium ions, substance P, bradykinin, prostaglandins, and other chemical mediators) that sensitizes peripheral nociceptors [136]. Resultant gene expression in the dorsal root ganglion leads to increased excitability in peripheral nociceptors, which results in an overall increase in nociceptive input to the spinal cord [136]. This prolonged afferent input (glutamate is considered the principle neurotransmitters of nociceptors in the CNS [137]) may result in an irreversible or reversible change in the excitability of central sensory neurons resulting in activation of voltage-gated channel receptors throughout the whole spinal cord and supraspinal centers in addition to the neural structures connected to the original site of the initiating lesion [138]. The resultant hyperexcitability of the CNS may lead to positive sensory signs such as allodynia and hyperalgesia [137]. Expansion of the receptive fields (cutaneous area innervated by a single spinal neuron [139]) of dorsal horn neurons has also been noted. This results in widespread pain being produced through excitation of the sensitized dorsal horns by afferent input produced outside the area of the initial injured region [136]. In conjunction with these findings, there is evidence that supraspinal modulation is disrupted; resulting in an imbalance of descending facilitatory and inhibitory signals [133,140]. This may explain the role of psychological distress and cognitive factors in contributing to the maintenance of chronic pain states [54]. 2.5 Measurement of Pain Processes in Chronic WAD Sensory hypersensitivity (or decreased pain thresholds) has been identified using quantitative sensory testing (QST) in various chronic painful musculoskeletal conditions such

45 as WAD, fibromyalgia, temporo-mandibular disorders, tension-type headaches and migraine [ ]. Sensory hypersensitivity over healthy tissues (especially in anatomical bodily regions remote to the site of injury) indicates the presence of CNS hyperexcitability [54]. Typically, the pain threshold, or occasionally the pain response after suprathreshold stimulation is assessed [144]. Several psychophysical studies add to evidence that CNS hyperexcitability is a clinical feature in individuals with WAD. QST has revealed both local and widespread sensory changes in individuals with chronic WAD [35,145,146]; with reduced pressure and thermal pain thresholds demonstrated [ ]. Participants with WAD also show less effective conditioned pain modulation [149], reduced computerized cuff pressure pain thresholds (facilitated temporal summation) [150]; increased pain [33] and reduced sensibility [151] to vibration stimuli and to differing electrocutaneous modalities [32,63, ]. Widespread pain was also reported by participants with chronic WAD following injection of intramuscular hypertonic saline, into either infraspinatus or tibialis anterior muscles [31,150]. Heightened bilateral responses to the clinical brachial plexus provocation test have also been identified and proposed to reflect augmented central motor responses [35,108,149,155]. These clinical research findings support the basic science research, indicating that central hyperexcitability is a feature of chronic WAD, however further research remains to be performed in this area, as other tests of perceptual sensory dysfunction (such as two point discrimination threshold), indicative of altered cortical mechanisms in other conditions (e.g. low back pain) have yet to be investigated in the WAD population [156,157]. Psychophysical tests require an alert individual s cognitive response and require appropriate attention and concentration for accuracy of results. In contrast, the nociceptive flexion reflex (NFR) is independent of a participant s cognitive response. The NFR is a spinal reflex of the lower limb that is produced by a painful electrical stimulation of a sensory nerve (usually the sural nerve) [158], eliciting a flexion reflex that is recorded by electromyography (EMG) in the hamstrings musculature (biceps femoris) [159]. Voluntary hamstring contractions to application of the electrical stimulus can be ruled out by the timing of this reflex, as a defined latency (reflex threshold) is required for production of this reflex (<150milliseconds) [159]. Thus, this reflex is free of a subject s cognitive response and is considered an objective electrophysiological parameter for quantifying the excitability of

46 spinal neurons [160]. The minimal electrical stimulus required to produce this reflex is considered to be the reflex threshold [154]. It has been shown that the threshold required to elicit this reflex in individuals with chronic WAD is lower than that measured in asymptomatic individuals indicating the presence of spinal cord hyperexcitability [63,154]. A recent study revealed that a lowered NFR threshold determined in all participants in the acute stage following injury, persisted in individuals with chronic moderate to severe disability at 6 months, but resolved in those who recovered or reported mild disability at 6 months [161]. In contrast, generalized sensory hypersensitivity (pressure and cold hyperalgesia) was only ever present in those with moderate/severe symptoms and remained unchanged throughout the study period. The authors suggested that different mechanisms underlie sensory hypersensitivity and NFR responses. It was also reported that initial levels of pain related disability were a unique predictor of persistent spinal cord hyperexcitability, and therefore it was possible that ongoing peripheral nociception following whiplash injury resulted in lower NFR thresholds [161]. As different mechanisms may underlie individuals clinical features, it would seem important to incorporate both measures of sensory hypersensitivity and spinal cord hyperexcitability in the body of research forming the thesis. Recently, studies have also demonstrated that sensory changes may be related to psychological factors in individuals with chronic WAD [63,162]. Correlations between pain catastrophizing, psychological distress and various QST measures including cold pain thresholds (CPT) [63]; heat pain thresholds (HPT), and sensory detection thresholds have been demonstrated [162]. These studies found no relationship between these psychological measures and PPT [162], catastrophization and the NFR threshold [63]. These findings indicate that although psychological factors are associated with some of the sensory features evident in WAD, the association is inconsistent; indicating that psychological features alone cannot explain the sensory manifestations of WAD. However, the role of these features needs to be considered to fully understand the clinical manifestations experienced by individuals with chronic WAD. The presence of sensory hypersensitivity in chronic WAD also appears to differentiate this condition from idiopathic non-traumatic neck pain. In one study, participants with chronic WAD demonstrated lowered pain thresholds to pressure, heat, and cold stimuli in areas both local and remote to the cervical spine, when compared to participants with chronic

47 idiopathic neck pain [146]. Both groups demonstrated local mechanical hyperalgesia in the cervical spine. It was proposed that the findings of isolated local hyperalgesia in the idiopathic neck pain group were indicative of peripheral sensitization resulting from local neck structure involvement, whereas the generalized hypersensitivity shown within the WAD group was indicative of augmented central pain processing mechanisms [146]. The people with chronic WAD did have higher reported pain and disability levels and a relationship between pain and disability levels and sensory disturbance has also been demonstrated in manual office workers with neck pain [163]. Thus, consideration of pain and disability levels is required and was measured in the research forming this thesis Summary of Changes in Pain Processing Mechanisms It is evident that the changes observed in the sensory system in individuals with chronic WAD occur across dermatomes within a particular body region and also are widespread across different body regions. Such widespread changes appear to be a result of abnormal or augmented central processing of afferent input, resulting in the altered sensory responses. These findings have been supported by two recent systematic reviews [164,165], with another systematic review supporting the presence of reduced NFR threshold in individuals with WAD [166]. This may explain the persistence of symptoms in individuals with chronic WAD. These changes do not appear to be present in chronic neck pain of nontraumatic onset. However, of relevance to this body of research, it has not been determined whether or not central hyperexcitability in chronic WAD is related to ongoing peripheral nociceptive activity from injured cervical structures or is self maintaining. 2.6 Neuromuscular and Movement Dysfunction in the Presence of Neck Pain Clinical Findings in WAD Varying changes have been observed within the neuromuscular system in individuals with chronic WAD. These can be broadly classified into morphological changes, behavioural changes (changes in motor control strategies) and sensorimotor dysfunction

48 2.6.2 Morphological Changes Magnetic resonance imaging (MRI) has revealed that individuals with chronic WAD have infiltration of fatty tissue in the cervical flexor [167] and extensor muscles [43,168]. The fatty changes are especially noticeable in the sub occipital region (rectus capitis major and minor and C3 multifidus; and longus capitis/colli at C2/3) [43,167,168]. It is postulated that the changes observed in this region of the cervical spine may be as a result of transformation of Type I slow-oxidative to Type IIB fast-glycolytic fibres [169], general disuse, denervation atrophy or inflammatory responses associated with injury [43]. Tissue biopsy has also revealed the presence of biochemical alterations in the upper trapezius muscles, consisting of higher interstitial interleukin and serotonin levels in individuals with persistent pain in the chronic stage of WAD [170]. It is apparent that ongoing pain and disability of chronic WAD is associated with significant morphological muscle changes in the cervical spine region that persists in individuals with chronic WAD Changes in Motor Control Reductions of strength and endurance of the neck musculature has been measured in individuals with chronic WAD, with a wide variation in values apparent, likely reflecting between-individual differences [ ]. Not only are there changes in strength and endurance in the presence of neck injury or pain, but re-organization of motor control strategies has been demonstrated in a range of cervical muscles whilst performing various activities. Evidence of the relationship between excitation of cervical nociceptors and a variety of changes in motor behaviour come from electromyographic (EMG) studies, predominantly after inducing experimental pain [ ]. For example, after intramuscular injection of hypertonic saline into the sternocleidomastoid (SCM) musculature, contraction of the cervical flexors resulted in pain-induced inhibition in the agonist splenius capitus muscle [176,177]. Likewise it was shown that SCM activity reduced during cervical rotation (agonist) with pain evoked in the splenius capitis muscles [178]. Thus, one reason for muscle re-organization may be to minimize the use of the painful muscle [175]. Altered patterns of cervical and shoulder girdle muscle recruitment have also been documented, both in automatic function [179] and whilst performing prescribed tasks

49 [64,180]. The cranio-cervical flexion test (CCFT) is one example of a task which illustrates the motor control deficits in the neck region. During this task, subjects are positioned in supine lying and asked to perform a gentle, progressive nodding of the head (cranio-cervical flexion) [39]. Cranio-cervical flexion is the primary action of the deep cervical flexors, (longus colli and capitis), with little contribution from the SCM muscles to this task [181]. Patients with neck pain disorders have been shown to have lesser ability to recruit the deep cervical flexor musculature when performing the CCFT and their motor behaviour changes to complete the task via a compensatory increase in activity of the superficial SCM and anterior scalene muscles [182]. Thus the superficial and deep muscles display an altered spatial relationship in the presence of neck pain. Changes in activity (increased on the non-dominant and decreased on the dominant side) have also been recorded in the upper trapezius muscles in individuals with chronic WAD during a functional pencil tapping task [40]. Likewise, muscles such as SCM and upper trapezius are slower to relax following a task [42,181]. In relation to automatic function, it has been shown that there is a delay in activation of the cervical flexor (both superficial and deep) muscles during voluntary arm movements, indicating that the anticipatory feed forward mechanism involving activation of these muscles is impaired [179]. Poor motor control could contribute to the persistence or recurrence of neck pain episodes [51], as despite resolution of pain and disability, longitudinal studies reveal the persistence of motor deficits [51,64] Movement Dysfunction Various movement dysfunction has also been demonstrated in individuals with chronic WAD, including loss of active cervical ROM [38,64,69,149,183,184] and reduced conjunct motion [185]. Dall Alba at al demonstrated that active cervical ROM discriminated between patients with chronic WAD and subjects with no history of neck complaint [38]. Reduced ROM is present within one-month of injury [64], and persists into the chronic phase of WAD [51,64]. Of interest, one study has shown that it is only the group with self-reported moderate-to-severe symptoms that continue to present with loss of ROM 2-3 years following the initial injury [51]. The motor control and movement dysfunction observed in individuals with WAD are common to neck pain disorders and are observed in individuals with chronic neck pain of

50 insidious onset [180] and across different sub-groupings (mild to moderate/severe pain and disability) of WAD individuals [13,64]. Although treatment of these dysfunctions (improvement in ROM and motor control/co-ordination) has proven beneficial in reducing pain and disability in studies of chronic WAD subjects [186,187], some degree of ongoing pain and disability remain in many subjects, indicating, not unexpectedly, that these deficits are not fully responsible for the persistence of symptoms [188]. It is unknown why these features persist in individuals with chronic WAD Sensorimotor Dysfunction Patients with chronic WAD commonly complain of dizziness and/or unsteadiness, episodic loss of balance [13,46] and visual disturbances [45,189]. Balance and postural stability [46, ], ability to accurately relocate head position [13, ] and occulomotor control have also been shown to be altered in many individuals with chronic WAD [45,47,189,194, ]. This may be due to dysfunction in the CNS, cervical spine, vestibular or ocular systems [207]. Afferent information from the vestibular, visual, and somatosensory systems converge in multiple areas within the CNS, which is important for general equilibrium, body orientation, and oculomotor control [208]. Thus, it follows that abnormal afferent input from these systems can result in abnormal sensorimotor control. One group of authors mused on the likelihood of medication, anxiety or secondary gain being possible causes of sensorimotor disturbance [209]. However, an experimental study found that balance deficits could not be attributed to medications, compensation or anxiety [46]. Thus, it is more likely, and more commonly reported that trauma to the cervical spine region and aberrant information from this region is the most likely cause of these symptoms [47,195, ]. Nociceptive afferent fibres from both joint and muscles affect the proprioceptive activity of muscle spindle afferent fibres [214]. In accord, greater joint repositioning errors (JPE) have been found in patients with both acute and chronic WAD, particularly in those with higher reports of pain and disability [13,64]. Individuals with chronic WAD with dizziness symptoms may also present with a positive Smooth Pursuit Neck Torsion Test (SPNTT), a test specifically developed to differentiate cervicogenic dizziness following whiplash injury [45]. An abnormal gain is measured when the neck is torsioned (i.e. trunk is

51 rotated left or right underneath the stationary neck, producing a relative neck rotation) whilst performing an ocular horizontal tracking motion (i.e. smooth pursuit motion to follow a visual target right and left) as compared to the gain measured when the neck is in a neutral position [45]. This test was able to discriminate individuals with chronic WAD from patients with vestibular or CNS disorders, spondylosis or fibromyalgia [189]. Treleaven et al, found that individuals with chronic WAD (with and without dizziness) had altered eye movement control utilizing the SPNTT, which was likely a result of increased aberrant afferent nociceptive input [47] Summary It is clear that motor deficits occur very soon after injury [42,64], and greater deficits are evident in those subjects with higher levels of pain and disability [64]. However; even in subjects who recover, motor deficits are observed to persist [51]. Whether these motor changes are due to distinct pathoanatomical lesions (arthrogenous muscle inhibition) or as a result of chronic pain is unclear in many cases [215]. This requires further investigation. The measures for this body of research to evaluate motor performance were chosen to reflect established measures in individuals with chronic WAD [64]. Active cervical ROM was selected as it is a commonly used outcome measure in individuals with chronic WAD. The CCFT was chosen to further evaluate the role of pain on muscle function and in respect of its previous use in individuals with chronic WAD [180]. 2.7 Psychological Features in WAD Various psychological features have been demonstrated in individuals with chronic WAD [67], including distress, anxiety, depression and fear of movement [48, ]. In a cross-sectional study, Nijs et al reported an association between personality traits (inadequacy, self-satisfaction and resentment), social support and poor functional recovery in those with chronic WAD [220]. In contrast, in a prospective study design, Radanov et al. found that distress was not related to factors such as personality traits or cognitive abilities, but more related to the initial pain intensity reported following the MVC [48,69]. Psychological distress is present soon after the MVC [67,221], with some level of psychological distress apparent irrespective of initial pain or disability levels [67]. Gargan et al. found that psychological disturbances were associated with reduced neck ROM at three

52 months post collision, indicating a relationship between the physical and psychological presentation of WAD [221]. Wenzel et al found that psychological distress was related to symptom persistence, with individuals in the acute phase after the MVC less likely to demonstrate anxiety and depression compared to those whose collision was more than two years previously [52]. These data suggest that ongoing distress in the chronic phase of WAD seems to be a consequence of persistent pain and disability [69,221]. However, a more recent large prospective population cohort study found that pre-existing psychological symptoms [222], and poor general health prior to the injury [223] increased the likelihood of reporting whiplash symptoms. These results were confirmed by a recent systematic review, which concluded that individuals may have a pre-disposing vulnerability to develop chronic WAD as a result of inter-relationships between various psychosocial factors [50]. There is evidence contrary to this view regarding the influence of pre-disposing factors. It has been found that whiplash-injured patients with ongoing pain and disability at three months report greater psychological distress and a poorer quality of life than individuals who have recovered from their initial injuries [221,224]. Notably those individuals who recovered did report initial distress but it resolved concomitant with the decrease in pain and disability [67]. This relationship between persistent pain/disability and distress is supported by other clinical data. Resolution of psychological distress occurred once an individual s persistent pain was resolved with radiofrequency neurotomy [225]. All injured people display some psychological distress, but in the context of neck pain, the presence of posttraumatic stress symptoms seems to be unique to those with poor recovery following whiplash injury [67]. Drottning et al. [226] reported that a posttraumatic stress response may occur in the initial presentation of symptoms (within hours) following a whiplash event; with symptoms shown to persist into the chronic phase of the condition [51,67]. Higher levels of posttraumatic stress symptoms are also related to moderate levels of pain and disability [227,228] and are a prognostic indicator for poor functional recovery [ ]. The presence of a specific diagnosis of posttraumatic stress disorder (PTSD) following whiplash is not uncommon [227,229, ], with a 12 months post injury prevalence of approximately 30% [239]. Chronic pain and PTSD often co-exist [ ], with an increasing recognition of a shared vulnerability between WAD and PTSD [244]. A recent preliminary randomized controlled trial (RCT) in individuals with chronic WAD

53 demonstrated that a cognitive behavioural intervention was successful in decreasing PTSD symptoms, together with decreasing levels of pain related disability; although there were no changes in pain intensity or sensory pain thresholds [234], thus providing partial support for the possibility that PTSD symptoms impact pain-related factors. Emerging evidence indicates that pain catastrophizing is also relevant in the presentation of WAD [50]. Catastrophization is defined as a negative orientation towards noxious stimuli [245], or actual or threatened pain [246]; and is associated with enhanced pain reports, disability [247,248]. It correlates significantly with anxiety, fear and depression [246]. In patients with WAD, catastrophizing is associated with poor mental health outcomes and adverse health effects [248,249]. Greater reductions in pain catastrophizing have resulted in increased return to work rates in individuals with WAD following a 10-week rehabilitation program targeting psychosocial barriers (pain catastrophizing, fear of movement/reinjury and perceived disability) [250]. There is debate on whether catastrophization is a stable (enduring) [246], or a dynamic trait, related to particular constructs such as pain [251]. Reduction of pain catastrophizing has been measured following total knee arthroplasty [252], but no data exists in the WAD literature as to the effects of pain on catastrophization. Fear-avoidance behaviour is common in patients with low back pain [253] and has also been studied in acute, sub-acute and chronic WAD [67,218,254,255] with conflicting results. Nederhand et al [218] and Nieto et al [255] found that initial scores on the TAMPA scale of kinesphobia (TSK) predicted the persistence of symptoms following the initial whiplash event, whereas Buitenhuis and colleagues found no significant association between fear of movement and duration of symptoms when the analysis was adjusted for variables of age, gender and pain intensity [254]. These contrasting results may be due to the different outcome measures used in the studies or that the TSK may not adequately reflect fear avoidance in individuals with neck pain. In order to address this problem, the Pictorial Fear of Activity Scale Cervical (PFActS-C) was developed. The PFActS-C includes a series of photographs of movements that place different biomechanical stresses on the cervical spine that may be threatening to patients with neck pain [256]. Sterling et al. found differences between individuals with chronic WAD with moderate to severe symptoms disability and those with milder disability when using the TSK as a measure of fear-avoidance behaviour [67]. The individuals with mild symptoms reported a reduced TSK score as their pain and

54 disability improved at the two-month mark. Similarly, the individuals with moderate to severe symptoms reported reduced TSK scores between three to six months, such that their scores did not differ from those individuals who reported full recovery [67]. Sensing that this may have been due to insensitivity of the TSK, a further prospective study was performed [257]. This revealed that the two questionnaires seemed to measure different outcomes. The PFActTS-C scale was predictive of loss of cervical motion; whilst the TSK questionnaire (together with initial pain intensity) was predictive of poor functional outcome at 6 months [258]. Sterling et al. examined this response further with a novel experiment utilizing a vest and electronic diary to investigate the relationship between activity levels, fear of movement, posttraumatic stress and whiplash-injury related pain [219]. This demonstrated that the relationship between trauma symptoms and pain perception was mediated by fear of pain. Physiological arousal associated with thoughts or reminders of the MVC was reported to have an immediate or short term (less than an hour) impact on perceived pain/symptomatology through activation of the fear network. Trauma related avoidance symptoms (rather than fear of pain) predicted decreased levels of activity [219]. A subsequent prospective study reproduced these results (using questionnaires), demonstrating that fear mediated the relationship between pain and disability over a 6 month period [259]. Other factors such as coping styles have also been investigated in WAD [50]. There is some evidence that individuals with passive coping styles recover less quickly after a MVC [260,261]. In contrast, other studies have found that coping styles were not predictive of outcome at 1-year following injury [262]. In the study finding the relationship between coping styles and recovery, depression acted as an effect modifier in the relationship, such that participants with depression and passive coping styles took approximately four times longer to recover than those with depression and less passive coping styles [260]. Depression is a common psychological feature of WAD and related to pre-existing mental health [263]. The early presentation of depression (i.e. at six-weeks following the MVC, approximately 40% reported the presence of depression) suggests that chronic pain is not responsible for these symptoms [263]. Thus, there appears to be a complex interaction between physical and psychological characteristics in individuals with chronic WAD [63,66,248,264]. This is supported by empirical evidence suggesting that functional improvement occurs in both physical symptoms

55 (reduced pain intensity) and psychological symptoms (reduced fear avoidance) with programs directed towards graded exposure [250,265]. There is interest in emerging psychological factors in WAD, such as perceived injustice [264,266], self efficacy [8] and beliefs and attitudes regarding expected recovery [247,267,268]. Their influence on pain and recovery are yet to be fully determined Summary of Psychological Features Research regarding the psychological features in chronic WAD continues to develop rapidly. However, it is still unclear whether the psychological features arise as a result of being involved in a traumatic event (MVC); the distress of having persistent pain and disability [52], pre-existing psychological issues or general health concerns [50], which are exacerbated by a stressful event [65] or other undefined factors. Further investigation of the interaction between psychological distress, post traumatic stress symptoms and pain catastrophization is required and warranted in defined sub-groupings of chronic WAD. Longitudinal studies would more clearly define the relationship between ongoing nociception, pain and disability and psychological responses

56 CHAPTER 3 The cervical facet joint as a nociceptive source in chronic whiplash associated disorders: Diagnosis, treatment and modulation of clinical features. The body of work in this thesis explores the role of ongoing peripheral nociception in the sensory, motor and psychological presentation of chronic whiplash associated disorders (WAD). This chapter presents a review of cervical facet joint pain and its diagnosis. An overview of treatment options for chronic WAD will be provided, with a focus on interventions for the facet joint. The possibilities for modulating the underlying physical and psychological manifestations of chronic WAD are discussed and an argument is made for such modulation in people who respond to diagnostic cervical medial branch blocks (MBBs) and progress to treatment via radiofrequency neurotomy (RFN). 3.1 Introductory Remarks The traditional biomedical model of illness assumes a direct relationship between nociception and pain. It is based on the premise that identifying and treating the source of the nociception will result in improvements in pain and disability [269]. However, the biopsychosocial model acknowledges the interaction between psychosocial factors and biological ones (including a peripheral nociceptive source) on an individual s expression of pain [269]. Psychological treatments have been recognized in other musculoskeletal disorders with persistent pain (such as low back pain, headache, and fibromyalgia) to be as effective as standard medical treatment [ ]. Despite many different interventions being applied to individuals with acute WAD (including multi-professional, multidisciplinary management), it has not prevented a significant proportion of individuals from developing chronic pain and disability [3,273]. It would be beneficial to understand the relationship between distinct pathoanatomical lesions (with resultant nociception) and the pathophysiological disturbances (altered sensory and motor findings) and psychological factors in chronic WAD. It would also be of interest to understand whether sensory, motor and psychological processes can be modulated when

57 nociception from an underlying pathoanatomical lesion is reduced (i.e. are these manifestations dependent on, or independent of, a peripheral nociceptive source?). As some of these features (such as cold hyperalgesia or posttraumatic stress symptoms) are prognostic of poor functional recovery [7,147,231], it is important to determine if these features can be reduced with effective treatment of underlying nociception, or if they are self-maintaining due to neuroplastic changes in the central nervous system [56], indicating that other treatments would be required for their management. The tenet of this body of research is that sustained nociceptive input from the periphery (especially in deep pain-generating structures), results in persistence of central hyperexcitability [54], motor dysfunction and psychological distress [225]. Sustained nociception may arise when there is persistent inflammatory pain or in chronic neuropathic pain [137,274]. In both cases nociception from the periphery is amplified by central hyperexcitability, which is itself maintained by peripheral nociceptive input. Reducing the peripheral input may allow the combined reduction of both the noxious input and central hyperexcitability [137]. Clinical studies have shown that patients with painful osteoarthritis of the hip demonstrate pressure and thermal hyperalgesia when compared with sex- and age-matched controls [275], but the hyperalgesia normalizes after arthroplastic surgery and subsequent pain relief. These findings implicate the role of ongoing afferent nociception in the augmentation of central pain processes. Similar sensory features are also evident in WAD and generally thought to occur as a result of central hyperexcitability [136,276]. The role of peripheral nociception in the persistence of central hyperexcitability is not clear [53-55], with possible self-maintenance arising from neuroplastic changes in the central nervous system [56]. Motor deficits in individuals with chronic WAD are common [39,42,64], with greater deficits observed in those with higher levels of pain and disability [64]. Ongoing motor deficits remain despite self-reported recovery [64]. It would be beneficial to know whether the presence (or not) of a nociceptive source modulates the physical motor manifestations in individuals with chronic WAD. Psychological distress has been shown to be related to ongoing pain and disability in individuals with chronic WAD [52,67]. Psychological distress may result from posttraumatic stress disorder (PTSD), affective disturbances, anxiety, depression and behavioural

58 abnormalities such as fear of movement [52,216,218]. It would thus seem logical that the modulation of pain has the potential to also modulate psychological changes in WAD. 3.2 The Facet Joint as a Source of Nociception in WAD Basic Science Experiments Research abounds regarding the capacity of the cervical facet joint to generate and potentially modulate widespread neck pain [23,24,26,28,225, ], as well as refer pain to the head and upper extremities [286,287]. Mechanoreceptors and free (unmyelinated nociceptive) nerve endings have been found within the cervical facet joint and in particular, the subsynovial and capsular tissue [279,284] that collectively cover the entire joint [288]. Neuropeptides involved with nociception (substance P (SP) and calcitonin-gene related peptide (CGRP)) [289,290] in the peripheral and central nervous system have also been measured in human cadaveric cervical facet joint capsules [279]. Numerous cadaveric studies have shown that excessive facet capsule strain during the whiplash injury exceeds strains experienced during normal neck bending [16,18,291]. These strains can be increased by head rotation [292]. The strains in both cadaveric and animal studies produce partial tissue rupture, but do not involve tissue failure (sub-failure). Thus, they replicate the strains observed in capsules during simulated whiplash loading [19,21], suggesting that capsule lengthening during whiplash is a potential mechanism of injury. Subsequent progressive capsular deformation and pain generation on the sensory neural response was investigated in a goat model [282]. A significant number of capsular nociceptive afferents were activated [282] at strain values similar to those experienced in the lower cervical spine during whiplash loading [18,95]. It has also been shown that inflammation of the facet joints leads to elevated baseline discharge and decreased thresholds of capsule receptors (peripheral sensitization) [282]. In the same goat model, high capsular strain damaged axons in the capsular tissue, which may lead to persistent pain [293]. These strains corresponded to those detected in the human capsule during whiplash loading [18,19,21]. Thus, deformation of capsular tissue has been shown to activate peripheral nerve tissue/axon in a goat model. Cadaveric dissection models (with muscle force replication) exposed to whiplash trauma has also revealed the possibility of human capsules exceeding this injury threshold [18,291]. Re-organization of collagen

59 tissue has also been observed following capsular distraction despite the absence of complete tissue failure (i.e. sub-failure) [294,295]. Pain can result from these capsular responses without major mechanical failure [282]. Thus, significant tearing and structural disruption of tissues (as observed in cadaveric dissection studies) [23], is not required for ongoing nociception. Tensile forces under different strain conditions (sham, low and high) have been applied to rat facet joint capsules to examine the relationship between cervical facet joint capsule injury and behavioural hypersensitivity [281]. Behavioural hypersensitivity (pain response) was measured by the number of times the animal s forepaw withdrew from the applied innocuous tactile stimulus (forepaw mechanical allodynia) after the tensile force was applied to the capsule. Despite no evidence of observed capsular damage (even microscopically) following these experiments, behavioural hypersensitivity was observed following a certain amount of distraction. In the high strain group, mechanical allodynia existed for 7 days. There was no evidence of mechanical allodynia between the low strain and sham groups and it was postulated that there may be a mechanical threshold for capsular injury that results in persistent pain responses [281]. In regard to clinical whiplash, the high strains applied were similar to those applied during simulated whiplash loading [95]. Thus, it was postulated that persistent pain responses following whiplash injury may result from subcatastrophic injury to the joint capsule. Subsequent experiments have also revealed that this mechanical allodynia likely happens if injury occurs to an intact facet capsule [296]. The combination of anatomical, mechanical and electrophysiological findings in these basic science experiments suggests that facet joint capsule stretch resulting from whiplash loading (which exceeds strains observed during normal neck bending [93]) has the potential to initiate physiological pain responses. In fact, a recent study in rats revealed the presence of ongoing central nervous system changes indicative of central sensitization following painful distraction of the facet joint capsule (presence of increased spinal cord substance P (SP) mrna and SP protein expression in the dorsal root ganglion when compared to non-painful distraction). Even a non-painful distraction (sham procedure) resulted in expression of SP protein in the spinal cord [297]. Thus, it appears that the presence of afferent nociceptive input, producing peripheral sensitization in the cervical facet capsule, could theoretically result in subsequent central sensitization (increased responsiveness of nociceptive neurons in

60 the central nervous system to their normal or subthreshold afferent input [298]); which may explain the symptoms commonly observed in individuals with chronic WAD [54]. These experiments in animals have also been extended to investigate neuronal discharge rate in the dorsal horn of a rat [299]. The authors suggest that excessive facet capsule stretch, while not producing visible tearing, can produce functional plasticity of dorsal horn neuronal activity and suggests that facet-mediated chronic pain following whiplash injury is driven, at least in part, by central sensitization Clinical Diagnosis of Facet Joint Pain The incidence of cervical facet joint pain in WAD is relatively high. A placebocontrolled prevalence study in patients with chronic neck pain following whiplash injury employing comparative facet joint blocks revealed that the prevalence of C2-C3 facet joint pain was 50%, with 49% of these patients also having lower cervical facet joint pain. Overall, the prevalence of cervical facet joint pain (C2-C3 or below) was 60% (95% confidence interval: 46-73%) [28]. A further study using controlled double-blind diagnostic facet blocks determined that the prevalence of cervical facet joint involvement was 74% (65-83%) in drivers who sustained a whiplash injury at higher impact speeds [60]. Studies have investigated the capacity of clinical procedures to detect a cervical facet as the origin of a patient s neck pain. One study comparing the findings of manual intervertebral segmental examination against that of diagnostic facet blocks demonstrated excellent reliability in confirming the presence or not of facet joint pain [300], but another study failed to achieve the same level of concordance [301]. A recent study has added to this body of knowledge by investigating the accuracy of a combination of physical examination findings in order to develop a clinical decision guide [302]. It was determined that a combination of positive findings with manual intervertebral segmental examination, cervical spine segmental palpation and extension-rotation test may assist with the diagnosis of facet joint pain (specificity = 84%). In addition, negative findings with manual spinal examination and/or segmental palpation suggests that the cervical facet joint is not the primary source of nociception (sensitivity = 92% and 94% respectively) [302]. Other physical examination methods have been evaluated in a study attempting to predict success of RFN (based on a prior successful response to a single diagnostic medial branch block) [303]. Paraspinal tenderness in the neck region was predictive of successful

61 outcome of RFN but facet loading, combining active rotation and/or extension movement was not predictive of success with RFN. Success was defined as greater than 50% pain relief six months after the procedure was performed [303]. Thus, the findings of manual intervertebral segmental examination are showing promise to assist in determining patient suitability for interventional procedures to the facet joint and providing direction towards which facet joint should receive the intervention. When a patient proceeds to RFN, determination for suitability of this intervention is guided by response to randomized, comparative (utilizing two different local anaesthetics with different duration of pharmacological action for each anaesthetic), or placebo-controlled diagnostic facet joint injections [283]. Diagnostic facet blocks in the neck have face validity and target specificity [57] together with construct validity [304]. The effectiveness of this technique has been determined by short-term relief of symptoms, improved cervical range of motion postprocedure and effective long-term follow-up [305]. Some authors [306,307] dispute this gold standard as not fulfilling appropriate methodological criteria of diagnostic test accuracy as per accepted guidelines [308,309], although two recent systematic reviews considered the diagnosis of facet joint pain by controlled local anaesthetic blocks as safe, reliable and valid [310,311]. In summary, the validity of facet joint injections is disputed; primarily in regard to the existence of a criterion reference standard, which would allow determination of whether a positive response to diagnostic blocks also accurately corresponds to an actual putative facet joint (whether it be via single injection, comparative injections or when performed within a placebo-controlled fashion). [307]. In acknowledgement of this refernce standard dilemma for the subjective experience of pain, whereby a physical criterion cannot be established, a set of criteria have since been established (based on Bradford-Hill criteria) to assist with development of a metric for validation and quantification of different diagnostic blocks [312]. Currently, two techniques are commonly employed within clinics to determine whether the facet joint is a source of pain for a patient with persisting symptoms following their whiplash trauma [313]. Firstly, injections of anaesthetic can be made directly into the facet joint (intra-articular) under fluoroscopic guidance once a contrast medium has been injected to ascertain diagnostic accuracy. Secondly, a MBB can be performed (under the same stringent conditions with utilization of fluoroscopy and contrast medium for

62 confirmation of needle placement and injection location) to anaesthetize the medial branch of the dorsal ramus. As the medial branch of the dorsal ramus innervates the facet joint and the associated facet joint above [314], two levels of the dorsal ramus need to be anaesthetized to implicate one individual facet joint as the underlying nociceptive generator. Two procedures are performed with two different anaesthetics on two separate occasions [305]. Different anaesthetics have distinct and different duration periods of effect; such that a patient s equivalent pain relief can be measured. This helps eliminate the presence of false positive findings that predominate with single block procedures [28,305]. Thus, a patient can be injected with lidocaine and then followed up with bupivacaine at a later date; as the duration of effect of these medications are consistent within an individual. An individual should have a longer pain response to bupivacaine [315]. A patient who has longer-lasting relief for bupivacaine in comparison to lidocaine has an appropriately positive response to this procedure, thus implicating the facet joint as the underlying pain generator. A definitive response is greater than 80% concordant pain relief for that facet joint for the duration of the anaesthetic [316]. Many clinical studies use a cut-point of 50% improvement in pain relief to control for concurrent spinal pathology [303]. For research studies investigating diagnostic accuracy, performance of placebo-controlled blocks are recommended, whilst in clinical environments, comparative blocks demonstrate high levels of specificity (88%), allowing certainty regarding low false positive rates [304] As previously mentioned, the diagnostic accuracy for a single injection has been questioned, with various authors demonstrating false-positive rates of between 27-63% when single blocks were used (for either intra-articular injection or MBB) [28,305]. This necessitates performance of controlled, double-block paradigms to determine if the facet joint is the source of an individual s neck pain. However, irrespective of whether comparative or placebo-controlled blocks are performed, there has been no demonstrable difference in predictive capacity of subsequent response to RFN [283]. It has also been shown that a patient s psychological profile (in this case, major depression) can affect the false-positive rates of diagnostic facet joint injections in the neck [317]. Thus, studies incorporating interventional radiological procedures need to consider the psychological profile of their subjects when evaluating the outcomes resulting from performance of these procedures

63 3.3 The Need for an Effective Treatment Solution for Chronic WAD Conservative Treatment Efficacy The treatment of chronic WAD presents challenges. A study incorporating multimodal treatment (manual therapy, exercise therapy and advice/education) for those with idiopathic neck pain and cervicogenic headache resulted in significant functional improvements [318], but a recent randomized controlled trial (RCT) using the same treatment approach in chronic WAD did not provide a similar level of overall benefit [186]. Preliminary results revealed that pain and disability levels improved with multimodal physiotherapy in many the patients with chronic WAD; however post hoc analysis demonstrated that those who did not respond (approximately 25% of the cohort) were characterized by the presence of a combination of mechanical and cold hyperalgesia [186]. This preliminary study has assisted in shedding light on individuals that may or may not respond to conservative care. Several clinical trials have also failed to substantially reduce pain and disability in chronic WAD [187,319] or decrease the incidence of transition to chronicity for patients with an acute whiplash injury [187,262,273, ], whether it involved multimodal therapy, multi-professional management or psychological intervention. One RCT demonstrated that exercise therapy is more efficacious than advice in patients with higher baseline pain intensity and disability status in individuals with chronic WAD, but only immediately after the intervention [187]. More recently, multimodal physiotherapy, incorporating exercises was demonstrated to be no more effective than advice [319]. Thus, when taken together, the results of these studies indicate that conservative care fails to provide significant long-term benefit for certain individuals with chronic WAD. These results may be explained by the heterogeneous nature of WAD; lack of subgrouping of individuals into appropriate treatment interventions; pre-existing risk factors for poor outcomes and inter-individual treatment responses [323]. Thus, conservative interventions have provided only modest benefit to patients enrolled in the trials [324] Efficacy of RadioFrequency Neurotomy (RFN) Given the modest benefits of conservative care, other treatment solutions are required for those individuals with chronic WAD. Currently, the only treatment that has reported total

64 pain relief for patients with chronic WAD is RFN [316,325]. RFN involves neurolysis of the medial branch of the cervical dorsal ramus. Pain relief following RFN has been reported to be independent of medication intake, psychological status, operator, electrode type, litigation and return to work status [225,326]. This procedure has proven to be efficacious in a randomized, double blind clinical trial comparing the effects of RFN to sham [61]. The pain relief is not permanent and the median time for return of pain to at least 50% of the pre-operative level has been demonstrated to be 263 days [61]. The procedure may be repeated with similar success [283]. McDonald et al demonstrated that RFN provided complete relief of pain in 71% of their cohort of patients with chronic WAD with cervical facet-mediated pain [327]. The mean duration of pain relief in their study was 422 days (if only successes were included) or 219 days (if failures were included). Either way, this is a significant improvement for most patients, given that the definition of failure was when a patient returned to 50% of their preprocedure symptoms. Barnsley and colleagues subsequently performed an observational study in which 80% of subjects with chronic neck pain obtained significant pain relief of median duration of 35 weeks [328]. The original study justifying the benefits of RFN [61] has recently been criticized on methodological grounds, especially in regard to possible inappropriate selection criteria, potentially confounding baseline differences between treatment groups, lack of effective blinding and the lack of short-term benefit in pain relief [329]. Despite these criticisms two systematic reviews conclude that the evidence available to support cervical RFN is fair [330,331]. Thus, RFN provides one efficacious treatment option for individuals with chronic WAD Other Considerations Despite the efficacy of RFN in successfully reducing pain in individuals with cervical facetogenic nociception, not everyone benefits [61,326,328]. There is a need to determine who does and does not respond to RFN, and if RFN can successfully modulate those features of WAD that are associated with persistent and chronic moderate/severe pain and disability levels. RFN studies have tended to concentrate on outcomes involving pain, opioid use, psychological distress and/or compensation status to help determine which factors may determine the success of the procedure [332]. Few studies have explored other factors that

65 may be associated with a lesser or poor response to the intervention. It has been found that in patients with chronic low back pain undergoing RFN, those reporting reduced life control, disturbed mood, negative self-efficacy, catastrophizing, high anxiety levels, inadequacy, and poor mental health tended not to respond to this form of treatment [333]. Patients reporting less pain and interference levels, positive expectations, and reasonable physical and social functioning, responded more favorably [333]. It was advocated that from both a clinical and a financial perspective, psychosocial evaluation and selection of patients seems appropriate, before applying RFN procedures for chronic low back pain [333]. Research in the neck region is lacking in this regard. Thus, psychological factors need to be considered when investigating the efficacy of RFN, together with the ability of RFN to modulate the other clinical features of chronic WAD. 3.4 Modulation of the Physical and Psychological features of WAD Despite the wealth of data now demonstrating the presence of sensory disturbances, motor and movement dysfunction and psychological distress in chronic WAD, little is known about whether or not these features can be successfully modulated and if such modulation would improve health outcomes. This section will explore what is known about the capacity to modulate these physical and psychological features, and also describe the gaps that currently exist in the literature which the body of research in the thesis will investigate Sensory Features Peripheral tissue damage results in excitation of central neurons [133]. The resulting hyperexcitability is responsible for amplification of the peripheral nociceptive signal and the significant neuronal plasticity within the brain and spinal cord [133]. There are a number of small studies that have investigated the influence of education [334], manual therapy [335,336] and acupuncture [337] on sensory measures. They have demonstrated slight improvements in measures of central hyperexcitability (mainly increased pressure pain thresholds - PPTs), but such improvements have been small and below those recognised as a minimal clinical detectable change [338]. It is unclear if the lack of effectiveness is due to small sample sizes of the studies, ineffective treatment doses, heterogeneity of participants or the inability of the intervention to successfully modulate the central hyperexcitability

66 Two studies have attempted to investigate the relationship between peripheral nociception and central sensitization in individuals with chronic WAD [32,339]. In one study, anaesthetic was injected into painful and tender points in muscles of the cervical spine. Neither the intensity of neck pain nor sensory hypersensitivity to electrical stimulation or heat pain tolerance (at local or remote bodily regions) was attenuated by anaesthetic injection into the painful areas. However, when examining each individual s responses, it was apparent that some patients did have a decrease in their neck pain intensity, whilst in others their pain increased [32]. A subsequent study investigated individual responses to anaesthetic injections into painful and tender neck muscles [339]. Statistically significant negative correlations were found between change in pain score and changes in PPT measurements performed at two different sites in the neck ( most painful site and non-painful site), but not at the toe [339]. Following anaesthetic injection, the most painful neck site experienced a decrease in PPT and an increase in pain; whilst at the distant non-painful neck site, an increased PPT and reduced pain was measured. The authors concluded that different mechanisms underlie hyperalgesia localized at areas surrounding the site of pain (i.e. region of secondary hyperalgesia) and hyperalgesia generalized to distant body areas (i.e. healthy tissue such as the toe in this study). It was proposed that ongoing nociception likely influenced central hyperexcitability and with it, pain perception. Thus, effective attenuation of peripheral nociception could provide a reduction in central hyperexcitability [339]. It was also proposed that the tender muscles may have been due to underlying facet-mediated pain, and thus injections into these muscles would not have effectively anaesthetized the nociceptive focus [32]. A recent pilot study in our laboratory utilized intra-articular diagnostic facet joint injections and confirmatory MBB in patients with chronic WAD to investigate whether central hyperexcitability could be modulated through reducing nociception of the cervical facet joints [62]. There were significant increases in PPTs at all sites, and significant decreases in cold pain thresholds (CPTs) at the cervical spine post-mbb (with concomitant greater than 80% relief in pain as measured by VAS). The individuals with chronic WAD showed evidence of widespread sensory hypersensitivity to mechanical and thermal stimuli (when compared to a healthy control group) which decreased following a decrease in peripheral nociception via facet joint blocks. As the effect of MBB is short-term (pain relief

67 for duration of local anaesthetic only); these measures were not expected to be maintained. This research did not consider psychological variables or more direct measures of central hyperexcitability (such as nociceptive flexion reflex: NFR) and whether these were modulated by the changes in pain and sensory measures observed. One study has investigated whether various physical measures can be modulated via RFN [340]. Significant improvement in cervical range of motion (ROM), cervical muscular isometric strength (of the male participants) and PPTs resulted following RFN [340]. However, several limitations were apparent in this longitudinal study. RFN was performed on a variety of structures in and around the neck (medial branch of dorsal ramus, C2 dorsal root ganglia and the suprascapular nerve) based upon patient-reported symptoms, clinical examination and imaging findings, without diagnostic procedures such as facet joint injections or MBB, thus potentially resulting in inappropriate patient selection for RFN. Other treatments received during the RFN intervention period (such as concurrent rehabilitation, psychological intervention or medication) may have confounded the results and were not documented. The results of this study do provide some support that nociception has a significant effect on certain patient outcomes but they need to be further evaluated and replicated in a well-designed study. It appears possible that sensory changes in chronic WAD may be able to be modulated through effective utilization of RFN when a clear controlled, diagnostic standard is met. As the effect of RFN is prolonged (in comparison to MBB) [283,328], it is possible that modulation of sensory changes that characterize chronic WAD may be achieved. The body of research in this thesis proposes to investigate the capacity of cervical RFN to modulate the sensory features of individuals with chronic WAD Movement and Motor Control Dysfunction Many studies have documented the presence of ongoing movement dysfunction in patients with chronic WAD [38,40,41,64,211,341]. Kasch et al. [183] reported that loss of neck ROM resolved within three months of injury in all individuals, irrespective of recovery status. However, if individuals are classified according to pain and disability levels, it was shown that those with persistent moderate/severe symptoms continue to lack neck ROM at 2-3 years post injury [51], whilst those who recover or report milder symptoms regain ROM within 2-3 months of injury [64]. This indicates the importance of sub-grouping individuals

68 based on pain and disability levels. Individuals with chronic WAD also demonstrate ongoing altered patterns of upper quadrant muscle recruitment. However, this occurs irrespective of pain and disability levels, even being apparent in individuals reporting full recovery [64]. Individuals with higher levels of pain and disability 2-3 years post MVC had greater deficits in motor function [51]. It is unclear whether these clinical features are related to ongoing peripheral nociceptive input from cervical structures originally injured such as the facet joints [339], although this is possible, given the improvements in ROM and strength that resulted following RFN in one study [340]. Resolution of pain from these underlying nociceptive structures through effective response to RFN would allow investigation into the mechanisms surrounding these movement deficits and assist with determining appropriate treatment options for those individuals with chronic WAD and persistent movement dysfunction Psychological Features Effective treatment of chronic neck pain through utilization of RFN has been shown to decrease psychological distress (measured with SCL-90-R or General Health Questionnaire- 12), in addition to pain [225,326,342]. Since the time of this study, additional psychological factors such as posttraumatic stress symptoms [228] and pain catastrophizing [248] have been shown to be common in chronic WAD and the effect of pain modulation via RFN on these factors has not been investigated. Posttraumatic stress symptoms and chronic pain often coexist [ ], with higher levels of posttraumatic stress symptoms also related to pain and disability [227,228]. Pain catastrophization also results in greater disability for individuals with chronic pain, irrespective of physical impairment [247,248,343,344]. Due to the relationship between these psychological factors and pain and disability in WAD, it is important to determine if they will improve with effective modulation of pain is, or whether other treatment strategies are required. 3.5 Conclusions The cervical facet joint is a common source of chronic neck pain in chronic WAD patients. Through the use of comparative diagnostic facet joint injections, it can be determined if the cervical facet joint is a source of nociceptive input. When appropriate, the patient can undergo RFN with the goal of obtaining more long-term pain relief of facet joint

69 mediated pain. RFN provides a method to further investigate the effect of modulating nociception and pain on factors such as central hyperexcitability, motor function and psychological factors. It is vital to know if modulating nociception from the cervical facet joint can affect these factors as it could direct new treatment approaches for the difficult condition of chronic WAD. The role of nociception and the effect of its modulation is the topic of this thesis

70 CHAPTER 4 This chapter presents the initial study of the thesis. It was first necessary to determine if the clinical manifestations (physical and psychological features) of individuals with neck pain arising predominantly from cervical facet joint nociception differed in any significant manner from individuals without facet-mediated neck pain and a healthy cohort of individuals. These features then formed the basis of the clinical manifestations that could possibly be modulated through later performed RFN. For clarification, the aim of this study was: 1. To examine a sample of individuals who did and did not respond to facet blocks (intra-articular facet joint injection followed by confirmatory medial branch block MBB) as well as healthy controls to determine whether there were differences in their physical and psychological features once the effects of the blocks had abated and symptoms had returned. Publications: Study 1: Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. A Comparison of Physical and Psychological Features of Responders and Non-Responders to Cervical Facet Blocks in Chronic Whiplash. BMC Musculoskel Disord 2013 Nov 4; 14(1):313 doi: /

71 4.1 Study 1 A Comparison of Physical and Psychological Features of Responders and Non- Responders to Cervical Facet Blocks in Chronic Whiplash Abstract Background: Cervical facet block (FB) procedures are often used as a diagnostic precursor to radiofrequency neurotomies (RFN) in the management of chronic whiplash associated disorders (WAD). Some individuals will respond to the FB procedures and others will not respond, which provides the guidance for suitability for RFN before usual symptoms return. Such responders and non-responders provided a sample of convenience to question whether there were differences in their physical and psychological features once the effects of the blocks had abated and symptoms had returned. This information may inform future predictive studies and ultimately the clinical selection of patients for FB procedures. Methods: This cross-sectional study involved 58 individuals with chronic WAD who responded to cervical FB procedures (WAD_R); 32 who did not respond (WAD_NR) and 30 Healthy Controls (HCs). Measures included: quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test); nociceptive flexion reflex (NFR); motor function (cervical range of movement (ROM); activity of the superficial neck flexors during the cranio-cervical flexion test (CCFT). Self-reported measures were gained from the following questionnaires: neuropathic pain (s-lanss); psychological distress (General Health Questionnaire-28), posttraumatic stress (PDS) and pain catastrophization (PCS). Results: Following FB procedures, both WAD groups demonstrated generalized hypersensitivity to all sensory tests, decreased neck ROM and increased superficial muscle activity with the CCFT compared to controls (p<0.05). There were no significant differences between WAD groups (all p>0.05). Both WAD groups demonstrated psychological distress (GHQ-28; p<0.05), moderate posttraumatic stress symptoms and pain catastrophization. The

72 WAD_NR group also demonstrated increased medication intake and elevated PCS scores compared to the WAD_R group (p<0.05). Conclusions. Chronic WAD responders and non-responders to FB procedures demonstrate a similar presentation of sensory disturbance, motor dysfunction and psychological distress. Higher levels of pain catastrophization and greater medication intake were the only factors found to differentiate these groups

73 4.1.2 Introduction Whiplash associated disorders (WAD) are defined as the variety of symptoms arising from an initial whiplash injury usually as a result of a motor vehicle collision (MVC) [2]. The costs associated with WAD are substantial [2,82,83] with the majority of costs incurred by those individuals who transition to chronicity [9]. Approximately 50% of those injured report pain and disability at 12 months following the initial event [3]. There is now extensive evidence demonstrating marked physical and psychological changes in individuals with chronic WAD. These include sensory disturbances of widespread hypersensitivity [31,32,35] and hyperexcitable spinal cord reflexes [63,154] indicative of augmented central nervous system nociceptive processing (central sensitization). In addition, motor disturbances such as movement loss and altered muscle recruitment patterns have been clearly demonstrated [180,189,200]. Psychological distress (including affective disturbances, anxiety, depression and posttraumatic stress disorder symptoms (PTSD)) is also common in individuals with chronic WAD [8,67,226]. From a pathoanatomical perspective, the cervical facet joint is a common source of nociception in the neck region in individuals with chronic WAD [26,28,60]. Effective treatment of facetogenic nociception has been demonstrated with RFN [61], and may offer benefit to individuals who do not respond to conservative treatment following whiplash injury [345]. Recent synthesis of the literature and systematic reviews provide moderate levels of evidence of facet blocks (FB) as being effective for determination of suitability for RFN [331,346,347], thus understanding the differences between those who do and do not respond to these procedures is important. Limited data is available describing individuals who do and do not respond to these procedures. Cohen et al. [303] demonstrated that responders to cervical RFN had greater midline tenderness and Wasan et al. [348] showed that high comorbid pscychopathology was associated with less pain reduction following a single MBB. However these studies have not included a wide range of measures reflecting the physical and psychological features consistently demonstrated to be present in chronic WAD. Some of the sensory, motor and psychological measures may influence responsiveness to these procedures. For example, central sensitization has been demonstrated to be a predictor of poor prognosis in individuals with musculoskeletal pain undergoing conservative treatment [186,349] and individuals

74 undergoing surgery [350]; whilst catastrophization predicts poor response to painful procedures [245,351] and increased pain and disability ratings post surgery [352]. The presence of posttraumatic stress symptoms has also been demonstrated to result in more frequent pain and poorer prognosis in headache patients [240]. This preliminary study examined a sample of individuals who did and did not respond to FB as well as healthy controls to determine whether there were differences in their physical and psychological features once the effects of the blocks had abated and symptoms had returned. It was hypothesized that those who did not respond would have greater sensory, sensori-motor and psychological features than the responders and both groups would be different to the healthy controls. Such information is important to inform future predictive studies and ultimately the clinical selection of patients for FB procedures Methods Design: This study was conducted in a tertiary spinal intervention centre in Calgary, Alberta, Canada. A cross-sectional study design was used to compare the clinical manifestations of two WAD groups: 1) WAD participants who responded to cervical facet joint double blockade and subsequently proceeded to, and were awaiting RFN (WAD_Responders); 2) WAD participants who failed to respond to cervical facet joint double blockade (WAD_Non- Responders); and a 3) healthy control group (HC). Individuals were admitted into the study at a time post-cervical facet joint injections when symptoms had returned and they reported were no different from those prior to receiving facet joint injections Participants: Inclusion Criteria: Consecutive participants were recruited from individuals aged years with WAD Grade II [2] of a duration > 6 months post MVC who underwent scheduled cervical spine facet double block procedures (for predominant neck pain) (Intra-articular block - IAB and MBB). Those who responded (>50% relief of neck pain) to both of the cervical facet double blockade procedures, and who were scheduled to progress to RFN entered as the WAD Responder (WAD_R) group. Individuals who did not respond to the initial cervical IAB procedure formed the WAD Non Responder (WAD_NR) group. Healthy control

75 individuals with no previous history of neck pain, whiplash injury or recent treatment for musculoskeletal pain (within previous 2 years) were recruited from advertisements placed around the spinal intervention centre. Exclusion Criteria: Individuals were excluded from the study if they were classifiable as WAD Grade III or IV [2], or sustained a concussion or loss of consciousness as a result of the trauma. They were also excluded if their general health status prevented them from undergoing cervical facet double blockade procedure or RFN (e.g. central or peripheral neurological dysfunction such as stroke; peripheral vascular disease or coronary artery disease; pregnant, psychiatric history), or if they were not fluent in spoken or written English. Healthy controls were also excluded on these general health status criteria and all participants were excluded if they had sought recent treatment (previous two years) for a musculoskeletal condition or had received previous treatment for neck pain prior to the MVC. All the participants were unpaid volunteers. Ethical clearance for this study was granted from the medical research ethics committee of the University of Queensland and the conjoint health research ethics board at the University of Calgary. All participants provided informed consent Instrumentation: Individuals underwent laboratory testing, including QST (pressure pain thresholds (PPTs), thermal pain thresholds, brachial plexus provocation test (BPPT) and NFR) and measures of their motor performance (range of motion (ROM) and CCFT. A full description of these tests is provided in Appendix 1. Questionnaires: Individuals also completed a series of questionnaires. Baseline measures included a description of symptoms, symptom dominance (unilateral or bilateral) and severity, collision parameters, treatments since the collision, compensation status, list of medications and demographic variables including gender, age, marital status, employment status, education level and duration of neck pain as per a standard clinical examination

76 The visual analogue scale (VAS) was used to measure neck pain intensity. The Neck Disability Index (NDI) [353], was utilized to measure neck-pain related disability, whilst the s-lanss [354] was used to determine if the pain was predominantly neuropathic in nature. The General Health Questionnaire 28 (GHQ-28) [355] was used as a measure of general psychological distress, whilst the four subscales were also investigated, those being: somatic symptoms, anxiety/insomnia, social dysfunction, and severe depression. Each item has a 4-point rating scale ranging from (0) to (3). The total scores can be used as a measure of psychological distress, with a higher score (>23/24) indicating greater distress. The Posttraumatic Diagnostic Scale (PDS) [356] was included to assess number of symptoms and symptom severity according to the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision; DSM IV TR) diagnostic criteria for PTSD. For every item, the frequency of the 17 PTSD symptoms is assessed on a 4-point Likert scale, ranging from 0 (never) to 3 (daily). The items referred to a 1-month period prior to the study period. A total symptom severity score (ranging from 0 to 51) is derived with larger scores indicating greater symptom severity. A probably diagnosis of PTSD is made only when a specified number of DSM IV criteria are met across symptom clusters. Pain catastrophizing was evaluated using the Pain Catastrophizing Scale (PCS) [245]. Each of the 13 items has a 5-point rating scale ranging from (0) not at all to (4) all the time and scores provide a total for the PCS. A total cut-off score of 30 reflects that an individual has clinically relevant pain catastrophizing [357]. For a full description of these questionnaires, including detailed scoring criteria and appropriate clinimetrics, please refer to Appendix 1. In both WAD groups, the following measures were completed: VAS, NDI, s-lanss, GHQ-28, PDS and PCS. In the HC group, only the GHQ-28 questionnaire was completed Procedures Patient Screening and Participant Group Allocation: The referring physician nominated the spinal level and side of the facet joint block based on the individuals clinical presentation which the interventional radiologist reconfirmed based on clinical findings, including established pain maps [126]. Patients underwent a diagnostic IAB. A 25-gauge spinal needle was advanced under fluoroscopic

77 guidance, into the target facet joint with the individual in the prone position. A small amount of nonionic contrast (0.5 cc of Omnipaque 300 Amerslan Health, Oakville, ON, Canada) was used to confirm needle position. Subsequently, an injection of 0.5cc of local anaesthetic (1% Bupivicaine; AstraZeneca, Mississauga, ON, Canada), and 0.5cc of corticosteroid (Celestone; Celestone Soluspan, Schering, Pointe-Claire, Quebec, Canada) was made into the target facet joint, until resistance was felt. If the contrast-medication mixture leaked from the joint, this was noted in the procedure report, as diagnostic specificity may be affected. During the post-injection follow-up period (a minimum of two hours), participants who reported a decrease in neck pain intensity of at least 50%, and concurrently reported a significant improvement in symptoms (of their main and familiar pain) for the duration of the anaesthetic were determined to have responded to the IAB. If pain returned within the following days or weeks, they underwent a second diagnostic cervical facet joint block, a confirmatory MBB as advocated for the diagnosis of facet joint pain [58,59,316]. The MBBs were only performed at a time when the familiar pain returned. If an individual had prolonged relief of pain (generally > 3 months) following the IAB, then confirmatory MBBs were not performed. As these individuals did not receive subsequent MBB, a diagnosis of facet pain could not be confirmed, and these individuals were not included in the study. The MBB involved the placement of a 25-gauge spinal needle, under fluoroscopic guidance, onto the medial branch of the dorsal ramus as it courses over the waist of the articular pillar at each spinal level. An injection of nonionic contrast material (0.5 cc of Omnipaque 300 Amerslan Health, Oakville, ON, Canada) was made to confirm needle position. Subsequently, 0.5 cc of 2% Lidocaine (AstraZeneca, Mississauga, ON, Canada), was injected onto the medial branch of the dorsal ramus. Both medial branches to the target facet joint were anaesthetized in order to effectively anaesthetize the joint [316]. For the purposes of this current study, the patient was assigned to the WAD_R group if they had a successful response to the MBB (>50% relief of neck pain) for the duration of the anaesthetic and agreed to participate in the study. If the first IAB block was negative, investigations were either terminated or initiated at another segmental level that might reasonably have been responsible for the pain. In this manner, blocks were continued until all such possible levels either proved negative or until a positive response was encountered. This practice was recently recommended to assist with diagnostic accuracy and in an attempt to

78 reduce the false negative rate [307]. Thus, these patients underwent procedures directed at their familiar pain, such that if their predominant symptom was upper neck pain, the upper cervical facet joints (C2-4) were injected, whilst if their predominant symptom was lower neck pain, then the lower cervical facet joints (C4-7) were injected [126]. If an individual had upper and lower neck pain, or mid-level neck pain, then all facet joints were injected (C2-7) to rule out the presence of facet-mediated pain. A negative response was defined as no relief of pain with any procedure. These individuals were subsequently assigned to the WAD_NR group. Clinically, this diagnostic pathway is used prior to consideration for RFN [62]. There is some discussion in the literature regarding the optimum percentage of pain relief an individual should experience to fulfill the operational definition of a successful response [303,358]. To our knowledge, only one study has investigated this response in the cervical spine, with no significant difference in outcomes reported in patients with either 50% or 80% pain relief after their diagnostic block [303]. While 80% relief of pain is cited as the reference standard for research purposes [310], many clinicians feel that 50% relief is clinically significant [359]. From a practical perspective, individuals with this response were historically noted in our clinic to successfully respond to future RFN. Study Measurements: Measurements occurred approximately one month following the failed IAB (for the WAD_NR group participants), or successful MBB (for the WAD_R participants). All participants attended the research laboratory at a time point following procedures whereby their familiar pain had returned to the level reported prior to receiving the procedures. On arrival at the research laboratory, all participants underwent an examination by an experienced physiotherapist with postgraduate qualifications to reconfirm their eligibility before inclusion in the study. Participants were given a written description of the study procedures and informed consent was gained before proceeding to the questionnaires and testing. Familiarization sessions were performed for each measure. Participants practiced all movements or instructions until they felt comfortable to proceed. After completion of the questionnaires, a standard protocol was used for the order of tests [184]. The participants were seated, the Fastrak sensors applied and ROM was

79 measured. The participants were then positioned supine, EMG electrodes were applied, and the CCFT was performed. For all of the following bilateral tests, the left side was measured first. PPTs were measured in the following order: tibialis anterior, median nerves and C5/6. Thermal pain thresholds were then measured over the cervical spine, HPTs followed by CPTs; followed by the BPPT. The NFR was the final testing procedure. The same examiner tested all participants. No feedback or cues were given to the participants regarding their performance on any tests Data Analysis Data were analyzed with Stata 9.0 statistical software. Based on our previous research [62], our statistical calculations indicated that this study required 26 participants (with 80% power at 5% level of significance) to adequately detect a minimally clinically important difference for the following physical measures: change in Tibialis Anterior PPT, change in CPT, or change in NFR threshold. Assumptions of normality, nonmulticollinearity, and homoscedasticity were tested through examination of histograms, box plot graphs, correlation matrices, and a plot of predicted to residual values, respectively. If the data were not normally distributed, transformation of the data was applied to interval data. PPT, NFR, CCFT and BPPT data required log transformation. If normality was not achieved following transformation (CPT, HPT), medians and interquartile ranges were generated. The Wilcoxon matched-pairs signedrank test was used initially used to determine within participant side to side differences and followed by the exploratory analysis for all the measures and in all groups. Where no side-toside differences existed (CPT, BPPT), the data from each side was compiled and averaged, with the mean compiled data used for analysis. Where side-to-side differences existed within groups for various measures, the mean measure of each side was analyzed between groups. There was a significant side to side difference in the WAD_R group for HPT (p=0.007). There was also a significant difference in PPT measurements between right and left cervical spine (p= 0.001) and Tibialis Anterior (p=0.04) Pin the HC group (p= 0.001). As a result, group analyses for these measures were performed for each individual test site performed

80 Chi-squared analysis was utilized to determine if there was a difference in proportions of individuals in the WAD groups with respect to compensation status, employment, education, marital status, number of bodily symptoms and above threshold scores for GHQ- 28, PCS, PDS and s-lanss. Multivariate analysis of variance (MANOVA) was performed to investigate the effect of group (WAD_R, WAD_NR or HC) on the following log-transformed measures: PPT and CCFT, and normally distributed ROM. One way analysis of variance (ANOVA) tests were used for log-transformed BPPT and NFR measures. Where there was a significant group difference, post hoc tests of simple effects were performed to determine where these differences occurred. Non-parametric Kruskal-Wallis rank tests were used to determine any significant group differences for CPT and HPT measures. Non-parametric tests were used to analyze group differences in the following ordinal-scored questionnaires where homoscedasticity was present, but normality was not achieved (GHQ-28: Kruskal-Wallis; PCS, PDS and s-lanss: Mann-Whitney). Differences between groups were analysed using a priori contrasts. Significance level was set at 0.05 with Bonferroni adjustments used (for normally distributed data); and the Least Significant Difference (LSD) in ranks was calculated if significance was achieved using the Kruskal-Wallis rank test [360] Results Participants Ninety individuals undergoing IAB injections fulfilled the inclusion criteria and agreed to participate (32 males, 58 females, mean age / (SD) years). Fifty-eight individuals responded to the cervical facet double block procedure (IAB and MBB: 18 males, 40 females, mean age / years) and formed the WAD_R group. The C5/6 facet joint was the most common symptomatic joint either alone or in combination with another joint (Table 4.1)

81 Group C2/3 C3/4 C4/5 C5/6 C6/7 (n) (%) (%) (%) (%) (%) WAD_R (58) WAD_NR (32) Table 4.1: The prevalence of cervical joints injected (n=90) Legend: WAD_R = WAD Responders; WAD_NR = WAD Non-Responders Thirty-two individuals did not respond to the IAB (14 males, 18 females, mean age /- 9.7 years) and formed the WAD_NR group. Thirty healthy individuals (9 males, 21 females, mean age /- 9.7 years) formed the HC group. Figure 4.1 demonstrates the flow of participants through the study

82 Intra-Articular Facet Joint Injection (IAB) (n=177) Excluded (n=53) Not meeting inclusion criteria (n=49) Other reasons (n=4) Inclusion Criteria Met (n=124) Fail (< 50% relief of pain) (n= 55) Success ( 50% relief of pain) (n=69) Diagnostic Medial Branch Block (MBB) (n=69) Declined to participate (n=23) Declined to participate (n=11) Success ( 50% relief of pain) (n=58) Assessed for Study (Analyzed) Non Responder (WAD-NR) (n=32) Assessed for Study (Analyzed) Responder (WAD-R) (n=58) Figure 4.1: Flow of participants through study Legend: WAD_R = WAD Responders; WAD_NR = WAD Non-Responders The median [range] duration of symptoms post whiplash was 42 [9 195] months. All participants received initial treatment following the MVC, consisting mainly of pharmaceutics (a combination of various medications such as over-the-counter analgesics, anti-inflammatories, anti-depressants, opioids and anti-convulsants Table 4.2) and various therapeutic treatments, including physiotherapy, massage therapy, acupuncture, and chiropractic

83 Medication WAD_R n = 58 (%) WAD_NR n = 32 (%) Anti- Inflammatory Over-thecounter Analgesics Anti- Convulsant Opioid Muscle Relaxant 9 16 Anti- Depressant (SNRI) 7 9 Anti- Depressant (TCA) 7 16 Table 4.2: Medication Use at Intake of Each Participant Legend: WAD_R = WAD Responders; WAD_NR = WAD Non-Responders; SNRI = Serotonin-Norepinephrine Reuptake Inhibitors; TCA = Tricyclic Antidepressants A greater proportion of WAD_NR individuals were taking each class of medication (Table 4.2). Thirty-four participants in the WAD_R group (59%) and 16 in the WAD_NR group (50%) were receiving conservative treatment at the time of participation in the study

84 Group Gender Age Duration of VAS NDI s-lanss (n) symptoms (% F/M) mean yrs median mths mean (+/- SD) mean (+/- SD) median (+/- SD) [Range] (0-100mm) (%) [IQR] WAD_R (58) 69% 44.3 (10.4) 44 [9 195] 59 (18) 42 (15) 11 [8-17] WAD_NR (32) 56% 45.4 (9.7) 34 [10 190] 63 (19) 47 (14) 13 [8-16] HC 70% 44.2 (30) (9.7) Table 4.3: The demographic characteristics of subject groups Legend: WAD_R = WAD Responders; WAD_NR = WAD Non-Responders; HC = Healthy Controls; VAS = Visual Analogue Scale; NDI = Neck Disability Index; s-lanss = self-administered Leeds Assessment of Neuropathic Signs and Symptoms; IQR = Interquartile Range There were no significant differences in gender or age between the three groups (p>0.2) and no differences in pain (VAS and s-lanss) and disability (NDI) scores between the WAD groups (p>0.1: Table 4.3). Twenty-nine participants in the WAD_R group (50%) and 19 participants in the WAD_NR group (59%) were involved in ongoing compensation claims but this difference was not significant ( 2 = 0.73,1 d.f.,p=0.39). Likewise there were no differences between the WAD groups with respect to the presence of other bodily pain (number of symptoms), education levels, marriage or employment status (p>0.1). WAD groups did not differ to the healthy control group in relation to education levels, marriage and employment status (p>0.1)

85 4.1.8 Physical Measures Pressure Pain Thresholds (PPTs) MANOVA revealed a significant difference between the three groups at all test sites (neck, median nerve and tibialis anterior: F 12,224 =4.71, p<0.001; Table 4.4). Post-hoc tests showed that both whiplash groups demonstrated lower PPTs at all sites compared with the healthy control group (F 6, 112 =9.53, p<0.001). There were no significant differences between the whiplash groups (F 6, 112 =0.71, p=0.64). Thermal Pain Thresholds (TPTs) Kruskal-Wallis Rank tests revealed a significant difference between the mean ranks of TPTs per individual (for both cold pain threshold (CPT) and heat pain threshold (HPT) measurements) among the three groups (H>18.9, 2 d.f., p<0.001; Table 4.4). Post hoc testing revealed that both whiplash groups demonstrated elevated CPT (LSD>30.2, p<0.05) and reduced HPT (LSD>30.7, p<0.05) when compared to the healthy control group. There were no differences between the two whiplash groups for either CPTs (LSD=5.2, p>0.05) or HPTs on either side of the neck (LSD<2.3, p>0.05). Brachial Plexus Pain Provocation Test (BPPT) ANOVA revealed significant differences between the three groups for elbow extension ROM (F 2, 100 =27.72, p<0.001; Table 4.4). Post-hoc tests showed that the WAD_R and WAD_NR groups demonstrated restricted elbow extension ROM when compared to healthy controls (p<0.001). There were no significant differences between the whiplash groups (p=0.87). Nociceptive Flexion Reflex ANOVA revealed significant differences between the three groups for NFR threshold (F 2, 116 =5.52, p<0.01; Table 4.4). Post-hoc tests showed that the whiplash groups required less current to elicit the reflex than the healthy control subjects (p<0.05). There were no significant differences between the two whiplash groups (p=1.00)

86 Range of Motion (ROM) MANOVA revealed significant differences between the three groups in ROM (F 8,228 =22,88, p<0.001). Post-hoc tests revealed that the two whiplash groups demonstrated significant less ROM compared to the healthy control subjects (F 4,114 =62.29,p<0.001). There were no statistically significant differences in ROM in any direction between the two whiplash groups (F 4,114 =1.09,p=0.37; Fig. 4.2). Figure 4.2: Comparison of cervical range of motion (means +/- SE) between groups Legend: HC = Healthy Controls; WAD_R = WAD Responders; WAD_NR = WAD Non-Responders; SE = Standard Error of the Mean Cranio-cervical Flexion Test (CCFT) MANOVA revealed significant differences between the three groups for EMG activity of the superficial neck muscles at all stages of the CCFT (F 10,224 =3.34, p<0.001). Post-hoc tests revealed significant differences between the whiplash and healthy control groups (F 5,112 =5.98, p<0.001). No statistically significant differences existed between the two whiplash groups (F 5,112 =1.7, p=0.14; Fig. 4.3)

87 Figure 4.3: Cranio-cervical flexion test performance (means +/- SE) across groups Legend: RMS = Root Mean Square; HC = Healthy Controls; WAD_R = WAD Responders; WAD_NR = WAD Non-Responder; SE = Standard Error of the Mean

88 Group (n) HC (30) WAD_R (58) WAD_NR (32) MANOVA 327 [ ] 171 [ ] 166 [ ] PPT_Cx (kpa) Med [IQR] L R p< [ ] 185 [ ] 149 [ ] Table 4.4: Median [Interquarterile Range] scores and p values for Sensory Measures PPT = Pressure Pain Threshold; kpa = kilopascals; Cx = Cervical; Med = Median Nerve; TibAnt = Tibialis Anterior; CPT = Cold Pain Threshold; HPT = Heat Pain Threshold; BPPT = Brachial Plexus Provocation Test; elb ext = elbow extension range of motion; NFR = Nociceptive Flexion Reflex; ma = milliamps; L = Left; R = Right; HC = Healthy Control; WAD_R = WAD Responders; WAD_NR = WAD Non Responders. PPT_Med (kpa) 336 [ ] 226 [ ] 231 [ ] Med [IQR] L R p< [ ] 249 [ ] 229 [ ] PPT_TibAnt (kpa) Med [IQR] L R 531 [ ] 315 [ ] 322 [ ] p< [ ] 337 [ ] 338 [ ] CPT ( C) Med [IQR] 3.5 [0-8.1] 19.7 [ ] 17.4 [ ] Kruskal-Wallis: p< [ ] 42.7 [ ] 44.2 [ ] HPT ( C) Med [IQR] L R 47.4 [ ] 41.7 [ ] 42.6 [ ] Kruskal-Wallis: p<0.001 BPPT ( elb ext) Med [IQR] 3 [0-9] 30 [18-40] 34 [24-44] ANOVA: p<0.001 NFR (ma) Med [IQR] 21 [10-38] 12 [8-18] 12 [8-16] ANOVA: p<

89 4.1.9 Psychological Measures The median scores, interquartile ranges and proportion of participants exceeding threshold scores for GHQ-28, PCS, and PDS for the three groups are presented in Table 4.5. Group GHQ-28 PCS PDS (n) % Score % Score % met criteria Severity Score 23 [IQR] 30 [IQR] probable PTSD [IQR] WAD_R 64% 24 16% 15 29% 7 (58) [19-32] [7-23] [2-13] WAD_NR 66% 28 50% 30 44% 12 (32) [21-41] [13-39] [5-20] HC 7% 14 (30) [10-16] Table 4.5: Median [Interquartile Range] scores of each group for psychological measures Legend: GHQ = General Health Questionnaire; PCS = Pain Catastrophization Scale; PDS = Post Traumatic Stress Diagnostic Scale; PTSD = Post Traumatic Stress Disorder; IQR = Interquartile Range; HC = Healthy Controls; WAD_R = WAD Responders; WAD_NR = WAD Non-Responders Both whiplash groups demonstrated significantly higher GHQ-28 total scores (H=38.2, 2 d.f., p<0.001) compared to healthy controls. There was also a significant greater proportion of whiplash individuals with generalized psychological distress (GHQ-28>23/24, p<0.001) - 64% of WAD_R individuals and 66% of WAD_NR individuals scored above threshold (>23/24), compared to 7% of controls. There was no significant difference in psychological distress between the two whiplash groups (LSD=8.1, p>0.05). There was no difference in the proportion of individuals in the two whiplash groups fulfilling the criteria for PTSD ( 2 = 1.90,1 d.f.,p=0.168) with 29% of WAD_R and 44% of WAD_NR group meeting the PDS criteria. The results also suggest that there is no

90 statistically significant difference between the post traumatic stress severity scores of the two whiplash groups (z=1.69, p = 0.09). There was a significantly greater proportion (( 2 = 12.22,1 d.f., p<0.001) in the WAD_NR group (50%) with elevated Pain Catastrophization scores (PCS 30) [357], compared to 16% in the WAD_R group. Significantly higher PCS scores were also reported by the WAD_NR individuals (z=2.7, p=0.006) Discussion Our hypothesis, that individuals with chronic WAD who did not respond to FB procedures (WAD_NR), would have greater sensory, sensori-motor and psychological features than responders (WAD_R) was largely rejected; with few between group differences demonstrated. However, the results did reveal that both WAD groups were different to the healthy controls (HC). Possible reasons for these findings are discussed. Our participants with WAD presented similar profiles to previous studies and support findings that chronic WAD demonstrates a complex clinical presentation including sensory hypersensitivity, sensori-motor dysfunction and psychological distress [30,66]. Pain and disability levels were comparable to other patients undergoing MBB [26,28,61,328]. Some individuals reported an extensive duration of neck pain, and although the literature indicates the episodic nature of neck pain over time [79], all individuals reported that their symptoms were attributable to an original MVC. In concert with other studies, our participants reported lower pain thresholds to pressure and thermal stimuli [51,145,148] heightened responses bilaterally to BPPT [108,155], reduced NFR thresholds [63,154], decreased cervical ROM [38,64,361] and impaired control of cranio-cervical flexion [39,64,180]. Our healthy control data were likewise similar to that previously reported [180,362,363]. The psychological profile of our whiplash participants is also consistent, with high levels of psychological distress [8,67], moderate post traumatic stress symptoms [364] and levels of pain catastrophizing [247] evident. The presence of sensory hypersensitivity likely reflects central nervous system hyperexcitability [136,161] indicating that similar nociceptive processes underlie the conditions of both groups. Higher levels of pain and disability have been associated with the presence of these sensory features in WAD [35] and 82% of our participants reported

91 moderate to severe levels of pain related disability. Thus, it could be expected that sensory hypersensitivity would be a feature of both groups irrespective of responsiveness to the joint block techniques. There were also no differences in measures of motor function between the two whiplash groups. Loss of neck movement and impaired performance on the CCFT are also features of other neck pain conditions including non-traumatic idiopathic neck pain and cervicogenic headache [38,365]. Whilst there may be some relationship with levels of pain and disability [64], the uniform presence of motor dysfunction across neck pain conditions suggest that our findings are not unexpected. Levels of psychological distress as measured with the GHQ-28 were no different between our whiplash groups and are not surprising considering the levels of pain and disability reported by the participants. Whilst not reaching statistical significance, a greater proportion of non-responders fulfilled the criteria for a PTSD diagnosis on the PDS questionnaire (44% of non-responders versus 29% of responders) and reported higher symptom severity levels. The lack of statistical significance may be a consequence of the sample size of the study and this factor requires further investigation, especially given recent studies that demonstrate a relationship between PTSD, and pain/disability in WAD [219,233,366]. There was one notable difference between the two whiplash groups. Higher levels of pain catastrophization were demonstrated in the WAD_NR group. Catastrophization has been associated with enhanced pain reports, concurrent disability [247,248] and lower pain threshold/tolerance levels, but is not significantly related to nociceptive flexion reflex (NFR) threshold in healthy and clinical pain samples [63,367]. Sullivan et al. [245] reported that higher levels of catastrophization predicted higher levels of pain following medical procedures, such that these individuals may actually be less responsive to invasive interventions. It is possible that the higher levels of catastrophization and tendency towards higher psychological distress and post traumatic stress symptoms observed in the WAD_NR group may have contributed to the lack of response to the facet joint injection. The exact mechanisms responsible for this lack of responsiveness require further investigation, but may even include diminished placebo responses, where individuals may not believe in the blocks or invasive procedures. Alternately, the higher PCS scores in our non-responder group may be a consequence of the study methodology. PCS scores were obtained following diagnostic

92 facet joint procedures in both whiplash groups. It is possible that a lack of response may increase levels of catastrophization. The WAD_NR group reported greater medication intake than the responder group and this was the case for all medication types. Given that pain and disability levels were no different between the groups, it could suggest that higher levels of catastrophization may explain the need for increased medication; or alternately, the lack of effectiveness of medication in reducing pain and disability may result in higher levels of catastrophization. There is some data available to support the initial claim suggesting that catastrophization is associated with greater medication intake [352]. However, this requires further investigation. The few differences found between the two groups in both physical and psychological measures would seem to indicate that similar processes are contributing to the clinical presentation, regardless of whether or not facet joint nociception is involved. It is possible that the WAD_NR group may have nociception arising from other structures. Cadaver and biomechanical studies indicate that various cervical spine structures can be potentially injured during whiplash trauma mechanisms and structures other than the cervical facet joints may be responsible for ongoing nociception [20,23,97]. However, it has also been proposed that factors other than peripheral nociception, for example physiological stress responses, can induce hyperalgesic responses and these may explain the presence of various symptoms in individuals with chronic WAD [65,368,369]. Future studies are currently underway to investigate the attenuation of the physical and psychological features of chronic WAD following modulation of facet joint nociception, to assist in understanding this relationship further. Wasan et al. [348] previously demonstrated that psychiatric co-morbidity is associated with reduced pain reduction following MBB, however they utilized different scales (Hospital Anxiety and Depression Scale); focussing on symptoms of anxiety and depression whereas this current study evaluated psychological distress (GHQ) and post traumatic stress symptoms (PDS). It may be that affective/anxiety symptoms have a greater association with response to MBB. Additionally, symptoms may not be as important as actual diagnosis in predicting response to MBB. There was certainly a trend towards an increased proportion of PTSD diagnoses in the WAD_NR group that may be of significance in a larger study. Therefore, further investigation of psychological diagnoses, and the role of pain catastrophization and

93 posttraumatic stress symptoms in outcomes following procedural interventions would be indicated. Consideration must be given to the diagnostic facet joint blockade procedures and cut-points used in our study. The use of comparative local anaesthetic blocks or placebo blocks has been advocated to guard against false positive responses [316]. In this study, two diagnostic injection procedures were used, IAB followed by MBB. This combination of diagnostic techniques possesses a similar construct to comparative MBB s, with individuals reporting relief of their predominant pain for the duration of the anaesthetic. Target specificity was ensured with each procedure by the use of radiographic confirmation of contrast medium (without note of radiate spread) to ensure needle location [370]. The responder patients in this study reported a consistent response to both procedures (50% or greater decrease in pain intensity). Whilst placebo blocks are preferred for ensuring diagnostic accuracy in the cervical region [304], this was not possible at the clinic where our study was conducted. Therefore, whilst the approach used in our clinic was stringent, we cannot fully exclude a placebo effect in responders or a nocebo effect in non-responders. A lack of differences between the whiplash groups may have also resulted from the criterion standard utilized in our study for determining success of the intervention. The clinic used in the study refers individuals for RFN if they report greater than 50% relief of pain following confirmatory MBB. This cutoff may not be sufficiently sensitive to detect differences between the responder and nonresponder groups. Eighty percent pain relief has been suggested for use in research studies [310], but our study was required to use 50% to adhere to the protocol required by the clinic involved. However, previous research has shown no difference in clinical outcomes following RFN when 50% versus 80% pain relief from FB was used as the criterion standard [303]. It was also noteworthy that more individuals who failed to respond to the MBB were lost to follow-up. As figure 4.1 demonstrates, 23/55 (42%) people who did not respond to IAB were lost to follow-up, compared to only 11/69 (16%) of those who responded. Comparison of these individuals was not possible and the effects on the results are not known. Another possible limitation of this study was that the measures performed in this study were performed by the study author, who was aware of the study hypotheses, however considerable

94 care was made to avoid describing study aims to the participants during the study (and expectations of results were unknown given it was a descriptive study); however bias is possible when examiners are not blinded. This study was a preliminary cross-sectional study to investigate any physical or psychological differences in a cohort of individuals with chronic WAD who did and did not respond to cervical FB procedures. The design has limitations, but the results serve to inform future predictive studies. Inclusion of the physical measures (i.e. sensory and motor measures) in future prospective studies, may be necessary for profiling patients, but is unlikely to be predictive of response. Our findings do suggest that a wider raft of psychological measures be explored, given some differences in these domains. In addition, the inclusion of measures such as locus of control, coping styles and expectations, may ultimately assist the clinical selection of patients for FB procedures Conclusion. Individuals with chronic WAD who respond and who do not respond to facet joint injections display similar complex clinical manifestations involving sensory disturbances, motor dysfunction and psychological distress. The presence of high levels of pain catastrophization and posttraumatic stress symptoms requires further investigation to determine their roles in non-responsiveness to FB

95 CHAPTER 5 In this chapter, the results of two studies are discussed. Study one demonstrated that individuals with facet-mediated neck pain following a traumatic whiplash injury presented with a complex array of physical and psychological manifestations. In study two, we investigated whether the physical manifestations could be effectively modulated by reducing nociception through the use of RFN; whilst study three investigated if the psychological manifestations could be modulated by the same procedure. The primary aims of these studies were: 1. To determine if the physical features of the clinical manifestations of individuals with chronic WAD arising from facet-mediated neck pain could be modulated by reducing nociception following RFN; 2. To determine if the psychological features of the same individuals could be modulated by reducing pain following RFN. Publications: Study 2: Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Cervical Radiofrequency Neurotomy Reduces Central Hyperexcitability and Improves Neck Movement in Individuals with Chronic Whiplash. Pain Med 2014;15(1): Study 3: Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Dunne-Proctor R, Sterling M. Cervical Radiofrequency Neurotomy Reduces Psychological Features in Individuals with Chronic Whiplash. Pain Physician (In Press)

96 5.1 Study 2 Cervical Radiofrequency Neurotomy Reduces Central Hyperexcitability and Improves Neck Movement in Individuals with Chronic Whiplash Abstract Objective: This study aims to determine if cervical medial branch radiofrequency neurotomy reduces psychophysical indicators of augmented central pain processing, and improves motor function in individuals with chronic whiplash symptoms. Design: Prospective observational study of consecutive patients with healthy control comparison. Setting: Tertiary spinal intervention centre in Calgary, Alberta, Canada. Subjects: Fifty-three individuals with chronic whiplash associated disorder symptoms (Grade 2). 30 healthy controls. Methods: Measures were made at four time points: two prior to radiofrequency neurotomy and 1- and 3-months post radiofrequency neurotomy. Measures included: comprehensive quantitative sensory testing (including brachial plexus provocation test); nociceptive flexion reflex; and motor function (cervical range of movement; superficial neck flexor activity during the cranio-cervical flexion test). Self-report pain and disability measures were also collected. One-way repeated measures analysis of variance and Friedman s tests were performed to investigate the effect of time on the above measures. Differences between the whiplash and healthy control groups were investigated with two-tailed independent samples t- test or Mann-Whitney tests. Results: Following cervical radiofrequency neurotomy there were significant early (within 1- month) and sustained (3-months) improvements in pain, disability, local and widespread hyperalgesia to pressure and thermal stimuli; nociceptive flexion reflex threshold, and brachial plexus provocation test responses as well as increased neck range of motion (all

97 p<0.0001). A non-significant trend for reduced muscle activity with the cranio-cervical flexion test (p>0.13) was measured. Conclusions. Attenuation of psychophysical measures of augmented central pain processing and improved cervical movement imply that these processes are maintained by peripheral nociceptive input

98 5.1.2 Introduction Approximately 50% of individuals who sustain a whiplash injury will continue to report ongoing neck pain and disability 12 months later [3]. Chronic whiplash associated disorder (WAD) is characterised by sensory disturbances (widespread hypersensitivity) [31,32,35] and heightened spinal cord flexion withdrawal responses [63,154], both indicative of augmented central nociceptive processing [56]. Changes in motor function are also evident with reduced neck range of movement and altered muscle recruitment patterns [38,180]. The processes underlying and contributing to these features are not clear. Whilst it is generally accepted that sensory features result from augmented central nociceptive processing (central hyperexcitability) [136,276], there is much debate as to whether these are driven by an ongoing peripheral nociceptive source [53-55] or are self-maintaining due to neuroplastic changes in the central nervous system [56]. Previous studies of patients with painful hip or knee osteoarthritis demonstrated improvement in sensory measures following successful arthroplastic surgery, indicating that central pain processes are being maintained by peripheral nociceptive input [275,371]. Similarly, persistence of motor changes following whiplash injury, such as morphometric muscular changes, local muscular weakness and loss of range of movement, suggests the presence of ongoing peripheral mechanisms [43,169,341,372,373]. However, these changes cannot be separated from changes in central nervous system control; with neuromotor performance in individuals with neck pain associated with reorganization of control strategies [176,177,179]. Whilst tissue damage usually cannot be detected in the patient with WAD with current imaging techniques, evidence to date suggests that a peripheral lesion of some kind is likely to be present [87,274]. Most available evidence would support the cervical facet joint as one source of nociception in individuals with chronic WAD [26,28,60]. Animal studies have demonstrated that cervical facet joint injury may be responsible for hypersensitivity and increased neuronal excitability [281,296,297,374]. Injury to the facet joint has also been implicated in local muscle responses in a cat model [214]. Modulating nociception from facet joints is possible via medial branch blocks (MBB) or radiofrequency neurotomy (RFN). There are suggestions that MBB or RFN may attenuate sensory hypersensitivity [62,340,375]; although the evidence is weak, with studies involving limited subjects, measures or

99 procedures; or only investigating immediate post-procedure effects. Thus the role of the cervical facet joint in regard to sensory and motor changes in chronic WAD requires further investigation, with a wider range of measures of central hyperexcitability, and inclusion of measures of motor function. The aim of this study was to investigate changes in measures of central hyperexcitability following RFN of cervical spine facet joints in individuals with chronic WAD. We also investigated changes in motor function following the same procedure. The null hypothesis proposed that reducing nociception via RFN would not result in changes in psychophysical indicators of central hyperexcitability or changes in motor function Methods Design: A prospective cohort study design was employed at a tertiary spinal intervention centre in Calgary, Alberta, Canada. Participants included individuals with chronic WAD who underwent RFN, following a successful response to cervical facet joint double blockade. A healthy control (HC) cohort was also investigated to provide comparative data. Individuals with WAD attended the research laboratory at four time points: one month following cervical facet joint injections (double blockade procedure), immediately prior to receiving RFN, one month following RFN, and three months following RFN. HC individuals attended one session of laboratory testing Participants: Inclusion Criteria: Consecutive participants were recruited from individuals aged years with WAD Grade II [2] of a duration greater than 6 months post motor vehicle collision (MVC) following successful response (greater than 50% of neck pain relief) to cervical facet joint blockade (intra-articular block followed by confirmatory MBB) [376], who subsequently underwent RFN. HC individuals with no previous history of neck pain, whiplash injury or recent treatment for musculoskeletal pain (within previous 2 years) were recruited from advertisements placed around the spinal intervention centre

100 Exclusion Criteria: Individuals were excluded from the study if they were classifiable as WAD Grade III (neurological deficit) or IV (fracture or dislocation) [2]; sustained a concussion or loss of consciousness as a result of the trauma; or if they were not fluent in spoken or written English. All the participants were unpaid volunteers. Ethical clearance for this study was granted from the institutional medical research ethics committees (University of Calgary and University of Queensland) in All participants provided informed consent Instrumentation: Individuals underwent laboratory testing, including quantitative sensory testing (pressure pain thresholds (PPTs), thermal pain thresholds (TPTs), brachial plexus provocation test (BPPT) and nociceptive flexion reflex (NFR)) and measures of their motor performance (range of motion (ROM) and cranio-cervical flexion test (CCFT)). A full description of these tests is provided in Appendix 1. Questionnaires: Individuals also completed a series of questionnaires. Baseline measures included a description of symptoms, symptom dominance (unilateral or bilateral) and severity, collision parameters, treatments since the collision, compensation status, list of medications and demographic variables including gender, age, marital status, employment status, education level and duration of neck pain as per a standard clinical examination. The visual analogue scale (VAS) was used to measure neck pain intensity. The Neck Disability Index (NDI) [353], was utilized to measure neck-pain related disability. For a fuller description of these questionnaires, including detailed scoring criteria and appropriate clinimetrics, please refer to Appendix Procedure: Participants were assessed on all outcome measures at the following time points: (t1) at a time period when their familiar baseline neck pain was present (when symptoms returned following successful cervical facet joint double blockade) [62]; (t2): immediately prior to receiving RFN; t(3)one month following RFN and t(4): 3 months following RFN

101 Attendance at two time points prior to receiving RFN allowed us to determine if time alone (t(1) vs. t(2)) resulted in improvements in measures, prior to RFN being performed. Participants first completed all questionnaires, after which a standard protocol was used for the order of tests [184]. The participants were seated, the Fastrak sensors applied and ROM was measured. They were instructed to assume a comfortable position looking straight ahead, then to perform each movement three times, moving at a comfortable speed as far as possible and to return to the start position between each repetition. The order of movements assessed were flexion, extension, left rotation and right rotation. The participants were then positioned supine, EMG electrodes were applied, and the CCFT was performed. For all of the following bilateral tests, the left side was measured first. PPTs were measured in the following order: tibialis anterior, median nerves and C5/6. Thermal pain thresholds were then measured over the cervical spine, HPTs followed by CPTs. These were followed by the BPPT. The NFR was the final testing procedure. The same examiner tested all participants. No feedback or cues were given to the participants regarding their performance on any tests RFN Procedure: Details of the RFN procedure are provided in Appendix Data Analysis Data were analyzed with Stata 9.0 statistical software. Based on our previous research [62], utilizing the standard deviation of changes observed (in distal PPT pre/post interventional procedure), our statistical calculations indicated that this study required 26 participants (with 80% power at 5% level of significance) to adequately detect a minimally clinically important difference for the primary outcome measures (change in PPT in Tibialis Anterior, change in CPT, or change in NFR threshold). Extra participants were recruited in the whiplash group to power a further study. Assumptions of normality, non-multicollinearity, and homoscedasticity were tested through examination of histograms, box plot graphs, correlation matrices, and a plot of predicted to residual values, respectively. If the data were not normally distributed, transformation of the data was applied. PPT, BPPT, NFR threshold and CCFT data required log transformation. Despite various transformations being attempted, normality for CPT and HPT was unable to be achieved (primarily due to floor and ceiling effects). A paired t-test

102 was used to determine within participant side-to-side differences for all measures and followed by the exploratory analysis for all the measures. As no side-to-side differences were found (PPT, CPT, HPT and BPPT), the data from each side were averaged and the mean data used for analysis. All assumptions for repeated measures ANOVA were satisfied, except for HPT and CPT. One-way repeated measures analysis of variance (ANOVA) was performed to investigate the effect of time (four levels: one month following cervical facet blockade; one month prior to receiving RFN; one month following RFN, and three months following RFN) on the following log-transformed measures: PPT, BPPT, NFR, and CCFT, and normally distributed ROM. Non-parametric Friedman s repeated measures test was used to analyze the effects of time on CPT and HPT. The baseline data for each dependent measure was entered into each ANOVA (but not Friedman s) analysis as a covariate. As this did not alter the significance of any of the results, further mention of baseline adjustment will not be made. For ease of interpretation, results are presented using non-transformed data for medians and interquartile ranges, with probability estimates taken from analyses using transformed data. Where there was a significant difference over time, post hoc tests of simple effects were performed to determine where these differences occurred. Significance level was set at 0.05 with Bonferroni adjustments used where appropriate. When the Friedman test was significant, multiple Wilcoxon Signed Rank tests were performed with Bonferroni adjustment (p < 0.008) utilized to determine where those differences occurred. Differences between the whiplash and healthy control (HC) groups were investigated with two-tailed independent samples t-test or Mann-Whitney tests (for CPT and HPT respectively). The data were assessed for effect size using Cohen s d for normally distributed data, and Cliff s Delta for non-parametric analyzed data [377]. The established convention rates were used. A Cohen s d effect size of 0 < 0.50 is small, a size of 0.50 to < 0.80 is moderate, and > 0.80 is large [378]. The corresponding effect sizes for Cliff s Delta are: < is small; between and 0.33 is moderate, and > 0.33 is large [379]. Effect size was calculated utilizing t(4), being the primary end point of this study; and t(2), the time period immediately prior to receiving RFN

103 5.1.5 Results Participants Fifty-eight individuals had a successful response to the cervical facet joint double blockade (intra-articular block followed by MBB) and agreed to participate in the study. Four individuals subsequently withdrew before undergoing RFN (three individuals declined to proceed with RFN, and one individual sustained other traumatic injuries from a skiing accident). Thus, 54 individuals underwent RFN. At the one month review period following RFN (t(3)), one individual sustained neuritis (this was the only side effect noted for the duration of the study); and thus was unable to attend for further analysis. Thus, 53 individuals (36 female, 17 male; mean age = / (SD) years) were included in the study. Three individuals were unable to attend the three month review (one pregnancy, two lost to follow up), although all data until that point was included in the analysis (Table 5.1). The collision vectors reported were: rear-end impacts (51%), frontal impacts (23%), side impacts (21%) and combined (6%) vectors. Twenty-eight participants (53%) were involved in ongoing compensation claims; 30 (57%) reported the presence of other musculoskeletal symptoms (i.e. headaches (44%), low back pain (34%), thoracic spine pain (21%), shoulder/arm pain (21%) and jaw pain (8%)); 27 (51%) were university educated; 41 (77%) were fully employed throughout the course of the study, and 39 (74%) reported that they were married or in a long-term supportive relationship. The median [range] duration of symptoms post whiplash injury was 43 [9 195] months (Table 5.1). Following the initial cervical facet double blockade procedure, there was a mean (+/-SD) wait of 10.4 (+/-4.5) months until RFN was performed. All participants received treatment following the MVC. Thirty-one participants (58%) were receiving conservative treatment at the time of participation in the study. Twenty-six participants (49%) had previously attended the local health authority multi-disciplinary chronic pain centre. The most common facet joint involved was C2/3 (41%), followed by C6/7 (28%) and C5/6 (24%). C3/4 (11%) and C4/5 (4%) were less often involved. Bilateral facet joint involvement was present in 31% of individuals, whilst 36% of individuals had involvement of both an upper cervical (C2-4) and lower cervical intervertebral segment (C4-7)

104 Following RFN, medication usage decreased as follows: anti-inflammatory medication (from 45% of individuals to 36%); simple over-the-counter analgesics (34% to 23%); various narcotic medications (26% to 19%); anti-convulsants (19% to 13%); selective serotonin reuptake inhibitors (13% to 8%), tri-cyclic antidepressants (13% to 6%), with slight increase in usage of selective norepinephrine reuptake inhibitors (8% to 13%). Gender Age Duration of VAS NDI (F/M) yrs (+/- SD) symptoms (+/- SD) (+/- SD) Mths (0-100mm) (%) median [25,75] WAD: WAD: 43 t(1): 58 (19) t(1): 42 (15) 36/ (10.9) [30,69] t(2): 55 (19) t(2): 43 (16) HC: HC: t(3): 25 (20) * t(3): 29 (16) * 21/ (9.7) t(4): 25 (21) * t(4): 27 (16) * Table 5.1: Demographics of participants and changes in pain and disability over time in the WAD participants Legend: WAD =Whiplash and Associated Disorder; HC = Healthy Controls; VAS = Visual Analogue Scale; NDI = Neck Disability Index; t(1) = time-point 1 (admission to study following cervical facet joint injection double blockade); t(2) = time-point 2 (immediately prior to receiving radiofrequency neurotomy); t(3) = timepoint 3 (one month following radiofrequency neurotomy); t(4) = time-point 4 (three months following radiofrequency neurotomy); p< (between t(1) and t(x)); * p< (between t(2) and t(x)); p=1.00 (between t(1 and 2), or t(3 and 4), or post-rfn) Pain and Disability Repeated measures ANOVA revealed a significant main effect of time for VAS (Table 5.1). Post-hoc tests of simple effects showed that there was no significant difference in pain scores before receiving RFN (t(1) and t(2)); with early (t(3): one month following RFN) and sustained (t(4): three months after receiving RFN) reductions in pain measured after receiving RFN. There were no significant differences in pain scores in the time periods following RFN. Similarly, there was a main effect of time for NDI scores (Table 5.1). Post-hoc tests mirrored

105 the results for VAS scores, with reduction in self-reported disability measured following RFN, with no significant differences in disability measured in the time periods prior to receiving RFN or following RFN respectively. The effect sizes were large for both pain (Cohen s d: 1.34 (95%CI: 1.13,1.55)) and disability measures (Cohen s d: 1.00 (95%CI: 0.79,1.21)) Pressure Pain Thresholds (PPT) Repeated measure ANOVA revealed a significant main effect of time for PPT at all sites (Table 5.2). Post-hoc tests of simple effects for the tibialis anterior and median nerve sites demonstrated early and sustained increases in PPTs following RFN; with no difference in PPTs observed prior to receiving RFN or following RFN. Similar results were demonstrated in the cervical spine site, with one slight difference, that being no significant difference measured between t(2) and t(3) (p=0.27). The effect sizes were moderate for all sites measured (Table 5.2). In comparison to the HC group, the independent samples t-test revealed that PPTs at all sites were lower in the whiplash group prior to undergoing RFN compared to controls (81 d.f., p<0.0001). Following RFN (t(4)), there was no differences between the WAD group and controls at the median nerve and tibialis anterior sites (78 d.f., p>0.18), but PPT at the cervical spine remained lower in the WAD group (t 78 =2.26, p=0.013) Nociceptive Flexion Reflex (NFR) There was a significant main effect of time for NFR threshold (Table 5.2). Post-hoc tests showed that there was no significant difference in NFR thresholds before receiving RFN. However, a significant difference was measured between the time periods prior to RFN, and following RFN, with increases in NFR threshold resulting following RFN. There were no significant differences in NFR thresholds between t(2) and t(4), and following RFN. The effect size was small: Cohen s d = 0.40 (Table 5.2). There was no significant difference between the healthy control group and the whiplash group at t(4): t 78 = 0.67, p=0.51. This compares to the significant difference in NFR threshold that existed prior to RFN being performed at t(2): t 81 = 2.97, p=

106 Brachial Plexus Pain Provocation Test (BPPT) There was a significant main effect of time for elbow extension ROM with the BPPT (Table 5.2). Post-hoc analysis revealed that there were no significant differences measured prior to RFN being performed. Increases in elbow extension ROM were measured following RFN. There were no significant differences in elbow extension motion measured following RFN. The effect size was large: Cohen s d: 1.21 (Table 5.2). The WAD group showed less elbow extension ROM compared to controls both prior (t 81 = -9.2, p<0.0001) to and following RFN (t 67 = -2.61, p=0.011; Table 5.2)

107 Time (n) t(1) (53) Cervical 186 [142,228] P values <----p= > t(2) (53) 199 [139,253] < p= > t(3) (53) 236 [178,304] t(4) (50) 293 [191,352] < p< > Healthy Controls 344 [285,415] Effect Size Cohen s d (95%CI) 0.74 (0.54,0.94) PPT (kpa) Median [IQR] NFR (ma) Median [IQR] Median N BPPT ( elb ext ROM) Median [IQR] < p< > 242 [183,286] <---p= > 253 [179,312] 307 [242,379] <---p= > 338 [252,426] 371 [297,428] < p< > 0.73 P values ---p= > < p< > (0.53,0.93) Tib Ant 328 [282,398] < p< > <----p= > 350 [285,436] 428 [363,549] <----p= > 511 [360,657] 563 [462,728] < p< > 0.73 P values <---p= > (0.53,0.93) < p< > 12 [6,18] < p< > 12 [6,20] 18 [10,30] --p=0.58--> <------p= > < p= > <---p= > < p= > < p= > <---p= > 29 [18,39] 31 [20,37] 12 [5,20] <----p= > < p< > <--p< > < p< > < p< > <--p=1.00-> 16 [8,38] 10 [3,19] 21 [10,38] 3 [0,9] 0.40 (0.20,0.60) 1.21 (0.98,1.44) Table 5.2: Summary of sensory measures over time in WAD participants vs. healthy controls

108 Legend: WAD = Whiplash and Associated Disorders; kpa = kilopascal; IQR = Interquartile Range; Median N = Median Nerve; Tib Ant = Tibialis Anterior; NFR = Nociceptor Flexion Reflex; ma = milliamperes; BPPT = Brachial Plexus Provocation Test; elb ext ROM = degrees of elbow extension Range of Motion; CI = Confidence Interval; Bolded P values denote statistical significance Cold Pain Thresholds (CPT) There was a significant effect of time for CPT (Table 5.3). Post-hoc analyses revealed that significant reductions in cold hyperalgesia (lower CPTs) were measured post-rfn. There were no significant differences in CPTs measured before receiving RFN or following RFN. Effect sizes were large: Cliff s Delta = Prior to undergoing RFN, the WAD group demonstrated a significantly elevated CPT (20.8 C) compared to the HC group (3.5 C, Table 5.3; Mann Whitney U = -4.89, n WAD = 53, n HC = 30, p<0.0001). At t(4), three months following RFN (in the WAD group), median CPTs in the whiplash group were significantly higher than those of controls (p=0.003; Table 5.3) Heat Pain Thresholds (HPT) There was a significant time effect for HPT (Table 5.3). Post-hoc analysis revealed that significant increased HPTs resulted following RFN. There were no significant differences in HPTs measured in the time periods prior to receiving RFN, or following RFN. The effect sizes were large: Cliff s Delta = 0.41 (Table 5.3). Prior to undergoing RFN, the WAD group showed lower HPT compare to controls (Mann Whitney U = 4.43, n WAD = 53, n HC = 30, p<0.0001; Table 5.3) but there was no difference between the groups following RFN (p=0.17; Table 5.3) being performed

109 Time (n) CPT ( C) Median [IQR] P values t(1) (53) 19.6 [11.3,25.3] <-----p= > t(2) (53) 20.8 [11.0,24.7] < p< > t(3) (53) 12.6 [4.9,17.8] <---p< > < p< > < p< > ---p= > t(4) (50) 9.7 [3.6,17.0] Healthy Controls 3.5 [0,8.1] Effect Size Cliff s Delta 0.38 HPT ( C) [40.3,45.0] [41.8,45.9] [43.7,48.1] [44.0,48.4] [46.1,48.6] Median <------p= > [IQR] < p< > 0.41 <---p< > P values < p< > < p< > <---p= > Table 5.3: Summary of thermal pain thresholds over time in WAD participants vs. healthy controls Legend: WAD = Whiplash and Associated Disorders; CPT = Cold Pain Threshold; HPT = Heat Pain Threshold; C = degrees Celsius; IQR = Interquartile Range; Bolded P values denote statistical significance Range of Motion (ROM) There were significant differences over time for ROM (F 3,153 =104.4, p<0.0001). Posthoc analysis showed no changes in ROM between t(1) and t(2) (p=1.00); however significant improvements in ROM were measured following RFN (both early: t(3) (p<0.0001), and three months later: t(4); p<0.0001). No significant differences in ROM were measured between t(3) and t(4) (p=1.00). A large effect size was present: Cohen s d: 1.78 (95%CI: 1.52,2.04). Both prior to and following RFN, the WAD group showed less ROM compared to the HC group (p<0.0001) Cranio-cervical Flexion Test (CCFT) There was a significant main effect of time for surface EMG at 24mmHg, 26mmHg and 28mmHg levels of the CCFT (Table 5.4). No significant effect of time was found for the 22mmHg and 30mmHg levels of the CCFT. Post-hoc tests of simple effects were not

110 significant. Thus, a general trend for reduced EMG was evident at the 24mmHg, 26mmHg and 28mmHg levels of the CCFT. Prior to RFN, the WAD group demonstrated increased EMG levels compared to the controls at all levels of the CCFT (p<0.05), except for 30mmHg (p=0.053). Following RFN, there was no significant difference between the WAD and HC groups for any level of the CCFT (p>0.084). Time t(1) t(2) t(3) t(4) ANOVA P value Healthy Controls 22mmHg [0.03,0.26] [0.04,0.15] [0.03,0.16] [0.02,0.15] [0.02,0.08] 24mmHg [0.05,0.31] [0.07,0.31] [0.05,0.21] [0.04,0.21] [0.03,0.19] 26mmHg [0.07,0.42] [0.14,0.66] [0.06,0.39] [0.05,0.28] [0.06,0.23] 28mmHg [0.15,0.52] [0.16,0.72] [0.12,0.53] [0.09,0.50] [0.10,0.30] 30mmHg [0.17,0.82] [0.21,0.86] [0.16,0.69] [0.10,0.71] [0.10,0.46] Table 5.4: CCFT RMS values (medians [IQR]) over time for WAD Participants vs. healthy controls Legend: mmhg = millimetres mercury; RMS = Root Mean Square; Bolded P values note statistical significance

111 Discussion The results of this study demonstrated that individuals with chronic WAD who underwent successful cervical RFN show significant and sustained reductions in sensory hypersensitivity (mechanical and thermal), spinal cord hyperexcitability, improved responses to the BPPT and cervical ROM with trends towards improved cervical muscle control. Attenuation of widespread sensory hypersensitivity, spinal cord hyperexcitability and measures of motor function after RFN suggests that nociception from the cervical facet joint contributes to augmented central nociceptive processing and movement dysfunction in patients with chronic WAD. Post-mortem studies have previously demonstrated that cervical facet joints are injured in MVCs [23-25,380], with clinical studies confirming the facet joint as a candidate for ongoing nociception in patients with chronic WAD [26,28]. Biomechanical studies of cadavers and human volunteers have demonstrated how these injuries may occur [14-21]. Animal studies have shown that facet joint capsule stretch resulting from whiplash loading [294] has the potential to initiate physiological and behavioural responses including nociceptive afferent activation and after-discharge [278,281,282,294,381,382]; release of inflammatory mediators resulting in peripheral sensitization [374]; and alterations in neuronal excitability in the spinal cord [297,299,381,383,384]. The results of our study, where hyperalgesic responses were effectively modulated following the reduction of facet joint nociception, would support the results of these animal studies demonstrating a relationship between the facet joint and ongoing hyperalgesic responses in WAD. Other studies in humans with chronic musculoskeletal pain have attempted to elucidate the relationship between peripheral mechanisms (persistent nociception) and augmented central processes. In studies of painful osteoarthritis, participants demonstrated central nervous system hyperexcitability prior to undergoing arthroplasty of the hip or knee which was reversed after arthroplastic surgery and subsequent pain relief [275,371], implicating the role of ongoing afferent nociception in augmentation of central pain processes. The influence of peripheral mechanisms driving central mechanisms was also demonstrated in a recent study involving individuals with chronic low back pain [385]. Following successful reduction in pain with surgery or facet joint injections; functional MRI scans demonstrated a reversal of functional and structural brain abnormalities, which did not occur in those who did

112 not respond to treatment [385]. Thus, it appears that successfully reducing nociception, results in changes in central pain processing mechanisms. Previous studies have investigated the effects of RFN on sensory measures in patients with WAD to some extent. Consistent with our findings, Prushansky et al. [340] and Chua et al. [375], demonstrated that PPTs measured over the cervical spine increased following RFN and this may reflect local hypoalgesia related to the anaesthetic procedure to the neck and decreased focal sensitization of peripheral structures. Our finding of decreased heat hyperalgesia may also support this proposal, as heat hyperalgesia is thought to reflect nociceptor sensitization, and also be an indicator of peripheral sensitization [362,386]. Chua et al. [375] found no change in PPTs at remote sites. In contrast, we found that PPTs at sites remote to the neck also increased, indicating that RFN has the capacity to modulate central as well as peripheral nociceptive processing. This discrepancy in study findings could be explained by the low sample size (n=9) of Chua s study [375], in view of large variance in distal PPT measurements [62,387]. We previously demonstrated immediate (within hours) increases in PPTs at sites away from the site of injury (neck) in patients with chronic WAD Given that conservative treatment has not reduced transition to chronicity for the WAD population [273] or reduced pain and disability in those with chronic WAD [319]; cervical RFN may be an option to assist with reduction of the global burden of WAD. The current study replicated these findings but demonstrated that these effects were sustained to at least three months post procedure and exceeded published minimal detectable changes (MDC) [338]. The current study findings also differed from those of our previous study. In the former study, PPT measures of the whiplash group remained lower than that of controls post- MBB, whilst in the current study, measures largely returned to those of the HC group. This may be due to the duration of pain relief in this study (3 months compared to 1-2 hours), or possibly due to participant variability in their health characteristics. In addition to changes in PPT, we found sustained increases in NFR threshold following RFN, indicating reduced excitability of the spinal cord reflexes; reduced hyperalgesic response to the BPTT, together with decreased cold and heat hyperalgesia. Cold sensitivity has been postulated to occur as a result of sensitized afferent fibres or dorsal horn neurons, with possible underlying insular cortex dysfunction [388,389]. Dorsal horn sensitization has also been suggested as an underlying mechanism of heat hyperalgesia [275],

113 whilst BPPT reactivity has been interpreted to reflect hyperalgesic motor and sensory responses as a consequence of central sensitization [155,390]. Thus, reduction of cold hyperalgesia, concomitant improvements in PPT at distal sites of uninjured tissues (tibialis anterior and median nerves), especially when combined with reduction of spinal cord hyperexcitability (increased NFR threshold) and improvement in BPPT hyperalgesia, would suggest that peripheral nociception contributes to these processes. Most of the sensory measures of the WAD group were no longer different from control data following RFN. The exceptions to this were CPT and BBPT responses, which remained more sensitive than the healthy controls at the follow-up time points, although the values for these two measures were within 95% confidence intervals of published normative data [35,391]. Individuals with chronic WAD consistently demonstrate the presence of persistent motor dysfunction [38,40,41,64,211,341], most noticeable in those with increased levels of pain and disability [38,64]. In longitudinal studies, motor dysfunction has remained unchanged over time [64,392], with only modest improvements in ROM, pain and disability demonstrated following a course of multimodal physiotherapy [186]. The changes measured were not significantly different to a self-management group (advice booklet and exercise) [186]. In contrast, our study demonstrated a large and significant improvement in ROM following RFN with concurrent large reductions in pain and disability. There was also a trend toward improvement in performance of the CCFT, with changes not quite reaching statistical significance. However, following RFN, no significant difference in test performance was measured between the HC and WAD groups, indicating that the improvements measured were relevant. Hence, the reduction of nociception resulted in certain CCFT improvements occurring. Given that individuals continued to report ongoing mild levels of pain, further improvement could be postulated to occur if further pain reduction was possible. However, these results are also consistent with findings in previous research, where, despite resolution of pain and disability in some participants, deficits in performance of the CCFT remained [64]. Thus, the remaining motor impairment in this group with chronic neck pain probably reflects both local changes in muscle properties as well as changes in central neuromotor control [176,177,179,372]. Individuals in our study continued to present with mild to moderate levels of pain and disability (as measured by VAS and NDI), one- to three-months following RFN. These

114 results are not inconsistent with other studies, when comparing similar time periods post-rfn [326,340]. At first glance, these results may not seem as promising as Lord et al. [61], where complete relief of pain was reported in the days following the procedure. In our study, 4 patients reported complete relief of pain 1-month following RFN and an additional 10 reported 1/10 pain. However, when comparing results at 3-months post-rfn, they are similar, with both studies finding that approximately 60% of participants reported relief of pain of at least 50% [61]. Pain reported at one and three months may be as a result of ongoing nociception from structures other than the facet joints influenced by RFN [27]. Additionally, ongoing disability found in our study could be related to factors such as persistent motor dysfunction (ongoing reduced ROM when compared to the healthy control participants and impaired motor control demonstrated via the CCFT) and persistent psychological distress [67]. There are some limitations in this study. We investigated 54 consecutive individuals undergoing RFN after successful response to facet joint double blockade. Selection of patients for, and performance of RFN differed slightly from the stringent guidelines established by the International Spine Intervention Society [393,394]. Another limitation of the study was that it was not possible to blind the assessor to the status of the patient or the aims of the study. This may have introduced bias, thus indicating some caution with interpretation of study findings Conclusions. Cervical RFN resulted in increased NFR thresholds, increases in local (mechanical and thermal) and remote (mechanical) pain thresholds as well as improvement in cervical ROM. These results indicate that augmented central nociceptive processes and movement loss are maintained by peripheral nociception arising from the cervical facet joints

115 5.2 Study 3 Cervical Radiofrequency Neurotomy Reduces Psychological Features in Individuals with Chronic WAD Abstract Objectives: To determine if reducing pain in the cervical spine (following cervical medial branch radiofrequency neurotomy - RFN) significantly reduces psychological features (distress, pain catastrophizing and posttraumatic stress symptoms) in individuals with chronic whiplash associated disorders (WAD). Methods: This prospective cohort study investigated 53 individuals with chronic WAD who underwent cervical RFN following successful response to cervical facet joint blockade. Measures were made at four time points: two prior to RFN, and one- and three-months post- RFN. Psychological measures included the General Health Questionnaire (GHQ-28); Pain Catastrophizing Scale (PCS) and the Post Traumatic Stress Diagnostic Scale (PDS). Selfreported pain (VAS) and disability (NDI) measures were also collected. Results: Pain, disability, psychological distress and pain catastrophization significantly decreased at both one and three months following RFN. There was no significant change in posttraumatic stress symptom severity (p = 0.39). Conclusions: Reducing pain via cervical RFN was associated with significant improvement in psychological distress and pain catastrophizing, but not posttraumatic stress symptoms. Effective pain relief would seem a crucial element in the management of psychological features associated with chronic WAD

116 5.2.2 Introduction Chronic WAD following a motor vehicle collision (MVC) are a significant public health problem that incur substantial personal and economic costs [2,82,83]. Psychological distress is common in many chronic pain conditions, [67,395,396] and chronic WAD is no exception. Psychological features which may be evident include: anxiety, distress, depression and posttraumatic stress disorder (PTSD) [48, ]. Relationships have been demonstrated between pain and psychological distress in individuals with WAD. Initial distress in those who recover will abate in parallel with resolving pain and disability [67,221,224]. In contrast, psychological distress remains elevated in those with poor recovery and ongoing pain and disability [51,52]. It has been demonstrated in patients with chronic WAD that pain relief following successful cervical radiofrequency neurotomy (RFN) resolves psychological distress and anxiety [225]. Relationships have not been examined between pain and a broader spectrum of psychological substrates now commonly identified in chronic WAD, such as PTSD and pain catastrophizing. Chronic pain and PTSD often co-exist [ ], with increasing recognition of potentially shared aetiological pathways of WAD and PTSD [244]. A recent study explored directional relationships between PTSD and chronic pain in 323 survivors of accidents (not whiplash) [397]. A mutual relationship was found between pain intensity and posttraumatic stress symptoms at five days post-injury; but by six months post-injury (chronic stage), PTSD symptoms impacted significantly on pain but not vice versa [397]. Further, a recent preliminary randomized controlled trial demonstrated that decreasing PTSD symptoms with a trauma-focused cognitive behavioral intervention resulted in decreased levels of pain related disability; with no changes in pain intensity or sensory pain thresholds demonstrated [234], thus providing partial support for the possibility that PTSD symptoms impact pain related factors. One way to further explore these relationships would be to modulate pain and evaluate effects on PTSD symptoms. To our knowledge such an investigation has not yet been undertaken. Catastrophization refers to an exaggerated negative orientation toward noxious stimuli [245]. Catastrophizing is associated with enhanced pain reports, disability [247,248], poor prognosis [398], and lower pain threshold/tolerance levels [63] in individuals with WAD

117 Treatment addressing catastrophization in individuals with WAD has demonstrated reductions in catastrophic thinking, however only modest improvements in pain and disability measured [250,399]. In contrast, reduced catastrophic thinking was demonstrated following successful knee joint arthroplasty, suggesting that catastrophizing is modulated by pain intensity [252]. We are not aware of studies in chronic WAD investigating the influence of modulating pain and its effect on pain catastrophizing. Cervical RFN is a neuroablative technique that denatures the sensory nerves of the cervical facet joints, resulting in reduction of nociception and related pain [61,328]. We have reported on a cohort of individuals with chronic WAD for whom RFN led to significant, and clinically relevant reductions in pain, disability, and sensory hypersensitivity and improved neck movement [400]. The aim of this study was to determine if psychological distress, pain catastrophizing and PTSD symptoms were modulated with the reduction in pain following RFN. We hypothesized that following pain reduction with RFN there would be concomitant reductions in psychological distress, pain catastrophizing and post-traumatic stress symptoms Materials and Methods Design: A prospective cohort study design was employed at a tertiary spinal intervention centre in Calgary, Alberta, Canada. Participants were assessed and completed questionnaires at the following time points: (t1) at a time period when their familiar baseline neck pain was present (when symptoms returned following successful cervical facet joint blockade) [376]; (t2): immediately prior to receiving RFN [400]; t(3)one month following RFN and t(4): 3 months following RFN Participants: Inclusion Criteria: Consecutive participants were recruited from: individuals aged years; with WAD Grade II [2] of a duration greater than six months post motor vehicle collision (MVC); who had had a successful response (greater than 50% of neck pain relief) to cervical facet

118 joint blockade (intra-articular block followed by confirmatory MBB) [376]; and who subsequently underwent RFN. Exclusion Criteria: Individuals were excluded from the study if they were classifiable as WAD Grade III (neurological deficit) or IV(fracture or dislocation) [2]; sustained a concussion or loss of consciousness as a result of the trauma; if they were not fluent in spoken or written English, had a major psychiatric history (e.g. psychosis, schizophrenia, bipolar disorder, etc) or previously treated for depression/anxiety. All the participants were unpaid volunteers. Ethical clearance for this study was granted from the institutional medical research ethics committees. All participants provided informed consent Outcome Measures: Questionnaires: As previously reported [376], a general intake questionnaire was provided to capture the details of collision related factors, symptoms and demographics of the participants. Measures of pain (visual analogue scale VAS) and disability (Neck Disability Index NDI, [353]) were also collected as reported [376,400]. All participants completed the General Health Questionnaire-28 (GHQ-28) [355] as a measure of general psychological distress. The GHQ-28 consists of 4 subscales, measuring 28 items of emotional distress in medical settings: somatic symptoms (items 1 to 7), anxiety/insomnia (items 8 to 14), social dysfunction (items 15 to 21), and severe depression (items 22 to 28). Each item has a 4-point rating scale ranging from (0) to (3). The total score provides a measure of psychological distress, with greater distress indicated by a higher score. The GHQ-28 has been used in previous research of WAD [67,221]. The Posttraumatic Diagnostic Scale (PDS) [356] was used to assess the presence of posttraumatic stress symptoms according to the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision; DSM IV TR [401]) diagnostic criteria for PTSD. Participants completed the questionnaire in relation to the MVC which resulted in their WAD injury. Using a Likert four-point scale, participants rated 17 items representing the cardinal symptoms of PTSD experienced in the past month. Finally, participants rated the level of

119 impairment caused by their symptoms across nine areas of life functioning. A probable diagnosis of PTSD is made only when a specified number of DSM IV criteria are met across symptom clusters. The PDS also includes a symptoms severity score which ranges from 0 to 51, obtained by adding up the individual's responses of the 17 symptom items. The cut-offs for symptom severity rating are 0 no rating, 1 10 mild, moderate, moderate to severe and >36 severe. The PDS has demonstrated high internal consistency and good stability and is a valid instrument for the assessment of PTSD in survivors of various traumatic events including MVC [402,403]. Pain catastrophizing was evaluated using the Pain Catastrophizing Scale (PCS) [245]. This 13-item questionnaire describes various thoughts and feelings that individuals experience when in pain, and indicates the degree to which each of the items applies to them, when reflecting on their past pain experiences. Each item has a 5-point rating scale ranging from (0) not at all to (4) all the time, with addition of these scores providing a total for the PCS. The PCS measures 3 distinct components: rumination, magnification, and helplessness [245]. Research indicates that the PCS is associated with heightened pain severity and has high internal consistency [404] Data Analysis Stata 9.0 statistical software was used to analyze data. To detect meaningful differences over time, power analyses were conducted to determine the number of participants required. Given the lack of previous research on these specific co-morbidities with utilization of these outcome measures, effect sizes were estimated from relevant previous research on catastrophization [250] and psychological distress [225]. Moderate-to-large effect sizes were estimated. On the basis of the previous research and in accordance with guidelines set out by Cohen [405], power was set at 0.80 and the significance level at Following collation of these results, it was determined that a minimum of 17 participants would be required to allow enough power to detect meaningful differences over time. Assumptions of normality, residual normality and sphericity were tested through examination of histograms, box plot graphs, and plots of predicted to residual values respectively. Normality was not demonstrated in the following questionnaire measures GHQ-28, PCS and PDS

120 For GHQ-28, PCS and PDS results (and their respective sub-components), nonparametric Friedman repeated measure tests were utilized to analyze differences over time. Significance level was set at Where there was a significant group difference demonstrated (over time), Mann-Whitney U tests were performed between each and every time point (six comparisons) to evaluate where the differences occurred. Bonferroni adjustment was used, such that the significance level was set at Chi-squared analysis was utilized to determine if there was a difference in proportions of individuals over time with above threshold scores for GHQ-28 (> 23) [355], PCS (>24) [399], and probable diagnosis of PTSD as determined by the PDS questionnaire [406]. The data were assessed for effect size using Cohen s d for normally distributed data, and Cliff s Delta for non-parametric analyzed data [377]. The established convention rates were used. A Cohen s d effect size of 0 <0.50 is small, a size of 0.50 to <0.80 is moderate, and >0.80 is large [378]. The corresponding effect sizes for Cliff s Delta are: <0.147 is small; between and 0.33 is moderate, and >0.33 is large [379]. Effect size was calculated utilizing t(4), being the primary end point of this study; and t(2), the time period immediately prior to receiving RFN Results Participants Figure 5.1 demonstrates the flow of participants through the study. This study investigated 53 individuals (36 female, 17 male; mean age = / (SD) years) who underwent cervical RFN. Three individuals failed to complete the study (one pregnancy; two lost to follow up). The median [range] duration of symptoms post whiplash was 43 [9 195] months. All participants received initial treatment following the MVC [376]. As previously reported, pain scores (VAS 0-100: mean +/- SD) were stable between t(1) (58 +/- 19) and t(2) (55 +/- 19) prior to the RFN but reduced significantly as measured at the two time points post- RFN t(3) (25 +/- 20) and t(4) value (25 +/- 21) [400]. Similarly, disability scores (NDI%: mean +/- SD) remained stable between t(1) (42 +/- 15) and t(2) (43 +/- 16), with significant improvement measured following RFN at t(3) (29 +/- 16) and t(4) (27 +/- 16) [400]

121 Enrollment Successful Cervical Comparative Blocks (X2) (n=58) Excluded (n=4) Declined to undergo RFN (3) Other trauma sustained (1) Pre-RFN measures t(1) Pre-RFN measures t(2) Allocation Radiofrequency Neurotomy (n=54) Excluded (n=1) Neuritis Follow-Up One Month Post-RFN (n=53) Post-RFN measures t(3) Analysis Excluded (n=1) Pregnant Lost to Follow Up (n= 2) Three Month Post-RFN (n=50) Post-RFN measures t(4) Figure 5.1: Flow of participants through the study Legend: RFN = radiofrequency neurotomy General Health Questionnaire (GHQ-28) The median scores, interquartile ranges and proportion of participants exceeding the threshold score ( 23) for GHQ-28 are presented in Table 5.5. The threshold score is indicative of presence of generalized psychological distress [355]. There was a significant effect of time, both in terms of proportion of individuals over the threshold score of 23/24 ( 2 = 14.8, 3 d.f., p=0.002), and their respective total scores ( 2 = 13.5,3 d.f., p=0.0012). Post-hoc analysis revealed a significant decrease in GHQ-28 total scores between t(1) and t(3) (p=0.0025); t(1) and t(4) (p=0.0002); t(2) and t(3) (p<0.0001); and t(2) and t(4) (p=0.0001), with no significant differences measured prior to undergoing

122 RFN (p=0.64), or following RFN (p=0.92). A large effect size was demonstrated (Cliff s Delta: 0.68). Immediately prior to undergoing RFN (t(2)), approximately two-thirds (64%) of the individuals had a total threshold score >23/24 (presence of generalized psychological distress), whilst three months following RFN (t(4)), only one-third (34%) of individuals recorded a score above this threshold; with the median group score reducing from 25 to 19 (below threshold) over the intervening period. Time GHQ-28 PCS PDS Period % Score % Score % met criteria Severity 23 [IQR] >24 [IQR] probable Score PTSD [IQR] t(1) 64% 24 [19,32] 19% 15 [9,22] 30% 7 [2,13] t(2) 62% 25 [17,37] 23% 17 [7,23] 34% 8 [2,14] t(3) 40% 17 [12,31] 13% 10 [4,17] 26% 5 [0,14] t(4) 34% 19 [12,26] 10% 8 [1,15] 16% 6 [2,11] Table 5.5: Median [Interquartile Range] scores for psychological measures over time Legend: GHQ = General Health Questionnaire; PCS = Pain Catastrophization Scale; PDS = Post Traumatic Stress Diagnostic Scale; t(1) = time-point 1 (admission to study following cervical facet joint injection double blockade); t(2) = time-point 2 (immediately prior to receiving radiofrequency neurotomy); t(3) = time-point 3 (one month following radiofrequency neurotomy); t(4) = time-point 4 (three months following radiofrequency neurotomy)

123 The median scores for the sub-component categories of the GHQ-28 are presented in Table 5.6 (somatic symptoms, anxiety/sleeplessness, social dysfunction and severe depression). In respect to the sub-component scores of the GHQ-28, there was a significant effect of time demonstrated in three of the four sub-components. Somatic symptoms ( 2 = 11.7,3 d.f., p=0.0029), anxiety/sleeplessness ( 2 = 7.99,3 d.f., p=0.018) and social dysfunction ( 2 = 14.5,3 d.f., p=0.0007) all demonstrated significant improvement following RFN. There was no significant effect of time for the depression subscale ( 2 = 3.8,3 d.f., p=0.14). GHQ-28 Somatic Anxiety/Sleeplessness Social Severe Depression Subscale Dysfunction Median Median Median Median [IQR] [IQR] [IQR] [IQR] t(1) [5,10] [4,10] [7,10] [0,3] t(2) [7,11] [4,10] [7,12] [0,3] t(3) [3,9] [2,8] [6,11] [0,2] t(4) [4,9] [3,7] [5,9] [0,1] Table 5.6: Median [Interquartile Range] scores for each sub-component of the GHQ-28 Legend: GHQ = General Health Questionnaire; t(1) = time-point 1 (admission to study following cervical facet joint injection double blockade); t(2) = time-point 2 (immediately prior to receiving radiofrequency neurotomy); t(3) = time-point 3 (one month following radiofrequency neurotomy); t(4) = time-point 4 (three months following radiofrequency neurotomy)

124 5.2.8 Pain Catastrophization (PCS) The median scores, interquartile ranges and proportion of participants exceeding the threshold score (>24) for PCS [399], are presented in Table 5.5. There was a significant effect of time for PCS scores ( 2 = 20.9,3 d.f., p<0.0001). Post-hoc analysis revealed a significant decrease in PCS scores between t(1) and t(3) (p=0.0001); t(1) and t(4) (p<0.0001); t(2) and t(3) (p<0.0005); t(2) and t(4) (p=0.0001); with no significant differences measured prior to receiving RFN (p=0.78) or following RFN (p=0.012). The demonstrated effect size was large (Cliff s Delta: 0.72). There was no significant difference in proportion of individuals over the threshold score of 24 ( 2 = 3.65,3 d.f., p=0.30). Immediately prior to RFN (t(2)), 23% of individuals had a total threshold score >24, whilst three months following RFN (t(4)), 10% of individuals scored above this schedule; with the median group score reducing from 17 to 8 during this time period Posttraumatic Stress (PDS) The median scores, interquartile ranges and proportion of participants meeting the criteria for a probable diagnosis of PTSD [406], are presented in Table 5.5. There was no significant difference demonstrated over time, in regard to proportion of individuals with a probable diagnosis of PTSD as measured on the PDS ( 2 = 4.68,3 d.f., p=0.20). There was also no difference in severity of posttraumatic stress symptoms for the group over time ( 2 = 1.90,3 d.f., p=0.39). There was no difference over time in regard to the number of posttraumatic stress symptoms demonstrated by individuals ( 2 = 2.24,3 d.f., p=0.33). At entry into the study (t(1)), 30% of individuals met criteria for a probable diagnosis of PTSD based on the scoring criteria of the PDS, which was essentially unchanged (26%) one month after receiving RFN. At three months following RFN, 16% of individuals fulfilled the PDS criteria for probable diagnosis of PTSD. In so far as the severity of symptoms were concerned, the group median score of 7 (at entry to the study) and 6 (three months post-rfn) equate to a mild level of stress symptoms being present [406]

125 Discussion Participants presented with initial moderate to severe levels of pain and disability and clinical levels of psychological distress, similar to previous studies of individuals with WAD [35,69], and individuals undergoing cervical RFN [61,326,340,342,407]. We have previously shown that cervical RFN led to significant, and clinically relevant, early and sustained reductions in their pain and disability; together with improved sensory and motor function [400]. In parallel, this study demonstrated reductions in psychological distress and pain catastrophizing post-rfn. No significant changes in posttraumatic stress symptoms were found post-rfn although there were trends towards reduced severity and number of symptoms, as well as a reduced proportion of individuals meeting criteria for a probable PTSD diagnosis. Our results are consistent with prior studies where reductions in psychological distress [225,340], anxiety [225], depression [340] and somatic symptoms [340] were demonstrated following RFN for patients with chronic WAD. In contrast, prospective data from noninterventional studies indicate that levels of psychological distress remain relatively consistent over time, with little evidence of fluctuation or resolution [48,51,52,221,224]. This differs from those with a resolving acute condition, who exhibit decreasing levels of distress that parallel decreases in pain and disability [67,221,224]. Results of the current study support the hypothesis that ongoing distress is associated with higher levels of pain. Levels of depression did not change significantly in the current study and this may reflect the instrument used, given that other studies have documented that depressive symptomatology after whiplash injuries is common [263], and predictive of poor prognosis [3]. The depression sub-scale of the GHQ-28 measures severe depression which was not a characteristic of our group. Our participants scored very low on this sub-scale at baseline, leaving little room for improvement and possibly resulting in a floor effect. Further research is needed using a more sensitive measure to evaluate the effects of pain relief with RFN on depression. Prior to RFN, 30-34% of our participants had a probable diagnosis of PTSD, based on the criteria of the PDS [408]. This is consistent with previous research indicating the prevalence of PTSD in chronic WAD to be similar to more major traumatic injuries requiring hospital admission [239]. The proportion of patients with a probable PTSD diagnosis decreased from 34% to 16% following RFN, although this was not statistically significant

126 Similarly, a small and non-significant decrease in PTSD symptom levels was found. This may also be due to a floor effect, given that participants reported only mild PTSD symptoms at baseline and post-rfn; but also may be a reflection of the sample size of the study; or indicate that PTSD symptoms are not as dependent upon pain levels as the other psychological substrates measured. In a prospective, longitudinal study following traumatic injury, Jenewein et al. [397] showed that in the chronic stage, PTSD symptoms impacted pain, but not vice versa. Our results support these findings as significant reductions in pain following RFN were not associated with significant reductions in posttraumatic symptoms. In addition, in chronic WAD, decreasing PTSD symptoms with trauma-focused cognitive behavioural therapy resulted in decreased pain related disability but not pain intensity or pain thresholds [234]. Thus, our non-significant results for PTSD when pain was targeted, and the inconsistent results on pain outcomes in Dunne s study [234], when PTSD symptoms were targeted, indicate that the nature of the relationship between pain and PTSD remains unresolved. Both our study and that of Dunne s are likely hampered by low sample size and future studies with larger samples are required. Taken together, these results may indicate that both pain and PTSD should be targeted in the management of chronic WAD. Treatment of underlying nociception to reduce pain (e.g. RFN), combined with treatment of PTSD (e.g. cognitive behavioural therapy) may be an option in the management of chronic WAD with identified facet joint involvement. There is debate on whether catastrophization is a stable (enduring) [246], or dynamic trait, related to particular constructs such as pain [251]. Individuals with chronic WAD presenting with pain catastrophizing demonstrate poor physical outcomes [63], concurrent disability [247,248] and poor prognosis [398]. When catastrophic thinking has been addressed (in work-disabled individuals with sub-acute WAD) through multidisciplinary rehabilitation [399]; physical therapy, or multi-faceted psychosocial risk factor-targeted interventions [250], reductions in catastrophizing have resulted, however with only modest improvements in pain and disability [250,399]. Approximately 20% of our participants presented with clinically significant catastrophic thinking. In contrast to the modest improvements in pain in other studies, our study demonstrated concurrent reductions in both pain and catastrophizing scores, with large effect sizes. It is also notable that the scores for catastrophizing following RFN (median score = 8) were substantially less than the post

127 treatment scores following physiotherapy (score = 14.0) or a 10-week program of physiotherapy combined with a multi-pronged strategy aimed at reducing psycho-social risk factors (score = 20.6) [250]. The significant reduction in pain following RFN was associated with substantial improvement in pain catastrophizing, similar to findings of a recent study of individuals undergoing total knee arthroplasty [252]. In combination, these findings support the proposal by Buitenhuis et al. [247], who argue that catastrophization likely results from high levels of pain and disability Thirty-four percent of individuals continued to report ongoing generalized psychological distress (GHQ-28) three months after receiving RFN. Whilst levels of pain related disability decreased significantly, the mean NDI score of the group indicated the presence of persistent mild to moderate levels in some individuals. This may be a reason for ongoing levels of distress. Alternatively the ongoing distress may be related to the other symptoms reported by over 50% of individuals in this study including headaches, shoulder/arm pain, thoracic spine pain and lumbar spine pain [376]. The reverse relationship may also exist, whereby ongoing psychological distress leads to persistent pain and disability [409]. Additional management addressing psychological distress may be required to further decrease pain and disability in this patient group. There are additional limitations of the current study that warrant discussion. Review of patients was limited to three-months post-rfn to allow investigation regarding the role of reduced pain on symptom presentation. Thus, the longer term effects of RFN on psychological manifestations cannot be established with this study. While patients completed the questionnaires independently, they were administered by the researcher who was aware of the aims of the study. Additionally, in order to minimise patient burden, we did not investigate other psychological factors shown to be present in WAD, such as self efficacy [8], fear of movement [258,259], coping styles [260,262,410,411], and beliefs and attitudes regarding expected recovery [247,267,268]. Investigation of these factors following RFN is warranted. Individuals in this study were also free to pursue treatment following RFN. Fifteen individuals attended treatment following RFN. One individual continued to attend the regional multidisciplinary chronic pain centre. Thus, the psychological improvements noted in this study cannot categorically be all attributed to RFN. However, given that these

128 individuals were receiving, and had received lengthy doses of treatment prior to RFN, without improvement in any measures documented between t(1) and t(2), we are confident that the results demonstrated can be attributed to the effects of cervical RFN. In summary, our results support the hypothesis that pain reduction following cervical RFN is associated with reductions in psychological distress and pain catastrophizing. Further research on the relationship between pain and post traumatic stress symptoms is warranted

129 CHAPTER 6 In the previous chapter, we demonstrated that the physical and psychological features of the clinical manifestations of individuals with chronic WAD could largely be successfully modulated following successful RFN of the cervical facet joints. This chapter reports on the results of a study investigating whether these same features recur upon resumption of pain, after the effects of the RFN abate and the pain returns. The main aim for this study was: 1. To determine if the physical and psychological features of individuals with chronic WAD change following the return of pain when the effects of cervical RFN have dissipated. Publication: Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Modulation of cervical facet joint nociception and pain attenuates physical and psychological features of chronic whiplash: a prospective study (Submitted for Publication Aug 15, 2014)

130 6.1 Study 4 Modulation of cervical facet joint nociception and pain attenuates physical and psychological features of chronic whiplash: a prospective study Abstract Objectives: We have previously demonstrated improvements in physical and psychological manifestations in individuals with chronic whiplash associated disorder (WAD) following cervical radiofrequency neurotomy (RFN). This study investigated changes in these features when the effects of RFN had dissipated and pain returned. Methods: A prospective cohort study of 53 individuals with chronic WAD who underwent RFN and were assessed prior and at one and three months post procedure. Measures included: quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test BPPT); nociceptive flexor reflex (NFR), and motor function (cervical range of movement - ROM; cranio-cervical flexion test - CCFT). Self-reported disability (NDI), psychological distress (GHQ-28), pain catastrophization (PCS) and posttraumatic stress disorder symptoms (PDS) were also measured. Results: Within one month of the return of pain following RFN, levels of disability increased (p<0.0001) and were no different to those prior to RFN (p=1.00). There was also a significant reduction in NFR threshold, increased cold hyperalgesia, increased responses to the BPPT, and reduced cervical ROM following the return of pain (all p<0.05) and all approached values recorded prior to RFN (p>0.22). There were no significant changes in local and remote hyperalgesia to pressure (p>0.054) or CCFT performance (p>0.07), following the return of pain. Psychological distress and pain catastrophization increased significantly following the return of pain (p<0.01) and again were no different than measures taken prior to RFN (p>0.13). However, there was no difference in number or severity of post-traumatic stress symptoms following the return of pain (p>0.30)

131 Conclusions: Physical and psychological features of chronic WAD are dynamically modulated with cervical RFN. These findings indicate that peripheral nociception is involved in the manifestations of chronic WAD

132 6.1.2 Introduction Many individuals transition to chronic pain and disability following whiplash injury from a motor vehicle crash (MVC) [3,51,69]. Chronic whiplash associated disorders (WAD) are characterised by psychophysical indictors of augmented central nervous system nociceptive processing [63,154], motor and sensori-motor dysfunction [180,189,200] and psychological features including posttraumatic stress symptoms, affective disturbances, anxiety and depression [8,67,226]. The mechanisms underlying these manifestations remain unclear. There is much debate about whether or not a patho-anatomical lesion is present in patients with WAD, as in the majority of cases such a lesion cannot be demonstrated with imaging. However evidence from biomechanical, basic science and clinical research indicates that there is likely to be an injury of some kind [87], with most evidence supporting cervical facet joint involvement [412]. We recently demonstrated that modulating peripheral nociception from the cervical facet joint via radio frequency neurotomy (RFN) attenuated measures of central hyperexcitability, improved neck range of movement and decreased psychological distress for up to three months [400,413]. These findings suggest that peripheral nociception from the cervical facet joints and/or associated pain contributes to the physical and psychological presentation of chronic WAD. When testing any model and implying the effects of such, the inverse should also apply. Pain relief following RFN is finite [283], with pain returning in the majority of cases over a period of 7 to 14 months [283,326,328,407]. The rationale for the return of neck pain relates to regeneration of the previously denatured nerve (medial branch of the dorsal ramus) [332,414], resulting in the ability to again transmit nociception, and henceforth the perception of pain. If central hyperexcitability, motor deficits and psychological distress of chronic WAD are indeed related to ongoing facet joint nociception, deterioration in the physical and psychological features would be expected to coincide with the return of pain. This study sought to determine, if there was: a) increased central nervous system hyperexcitability; b) reduced motor function, and c) increased psychological manifestations following return of pain after successful RFN

133 6.1.3 Materials and Methods Design: A prospective cohort study design was employed at a tertiary spinal intervention centre in Calgary, Alberta, Canada. Participants included individuals with chronic WAD who successfully responded to cervical facet joint double blockade [376], before proceeding to RFN [400]. Participants were assessed on all outcome measures at the following time points: (1) when familiar baseline neck pain returned following successful cervical facet joint double blockade [376]; (2): immediately prior to receiving RFN; (3): one month following RFN, (4): 3 months following RFN, and (5) when neck pain returned. Participants were contacted on a monthly basis following the three month review appointment and a structured interview was performed. When the participants determined that their familiar neck pain had returned to the same pain intensity as prior to receiving RFN (for a minimum period of low-fluctuating pain intensity of one week duration), they re-attended the research laboratory to complete the study (t5). We have previously reported the results of time periods 1 to 4 [400,413]. As there were no significant differences in measures for the two time periods prior to receiving RFN (i.e. 1 and 2) or the two time periods following RFN (i.e. 3 and 4), the results for periods one and two were averaged, as were the results for time periods three and four. Thus, this study is reporting the results following the return of pain t3 in relation to the following time periods: t1: prior to RFN and t2: post-rfn Participants: Inclusion and Exclusion Criteria: These criteria did not differ from studies 2 and 3 and are documented under sections and on pages 96 and 114 respectively Instrumentation: Individuals underwent laboratory testing, including quantitative sensory testing (TPTs, PPTs, BPPT and NFR) and measures of their motor performance (range of motion (ROM) and CCFT). A full description of these tests is provided in Appendix

134 Questionnaires: Participants completed standard intake examination forms, which collected information regarding demographics, MVC collision dynamics, symptom presentation and treatment history. These results have been previously reported [376]. Measures of disability (Neck Disability Index NDI, [353]) were also collected as reported [376,400]. Psychological distress was measured using the total score of the General Health Questionnaire-28 (GHQ-28) [355], as has been previously been reported [376,413]. The Posttraumatic Diagnostic Scale (PDS) [356] assessed the presence of posttraumatic stress symptoms (in relation to the MVC that resulted in their WAD injury) according to the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision; DSM IV TR) diagnostic criteria for post-traumatic stress disorders (PTSD). Participants rated the level of impairment caused by their symptoms across nine areas of life functioning. When a specified number of DSM IV criteria are met, a probable diagnosis of PTSD is made. The symptoms severity score was also calculated. We have utilized this scale before [376,413]. The total score of the Pain Catastrophizing Scale (PCS) [245] was used to measure pain catastrophization, as previously reported [376,413]. For a fuller description of these questionnaires, including detailed scoring criteria and appropriate clinimetrics, please refer to Appendix Procedure: The initial diagnostic work-up (Chapter 4.1.4), RFN procedure (Appendix 2) and study procedure (Chapter ) has been reported [376,400] Data Analysis Data were analyzed with Stata 9.0 statistical software. Based on our previous research [62], utilizing the standard deviation of changes observed (in distal PPT pre/post interventional procedure), our statistical calculations indicated that this study required 26 participants (with 80% power at 5% level of significance) to adequately detect a minimally clinically important difference for the primary outcome measures (change in PPT in Tibialis Anterior, change in CPT, or change in NFR threshold)

135 ANOVA assumptions were tested through examination of histograms, box plot graphs, correlation matrices, and plots of predicted to residual values, respectively. PPT, BPPT, NFR threshold and CCFT data required log transformation to achieve normality. The data from each side (PPT, CPT, HPT, BPPT) were averaged, with the mean data used for analysis. All assumptions for repeated measures ANOVA were satisfied, except for GHQ-28, PCS and PDS measures. One-way repeated measures analysis of variance (ANOVA) was performed to investigate the main effect of time (three measures: prior to receiving RFN; one to three months following RFN, and one month following the return of pain when the effects of RFN had worn off ) on the following log-transformed measures: PPT, BPPT, NFR, and CCFT, and normally distributed CPT, HPT, ROM, VAS and NDI. Non-parametric Friedman s repeated measures test was used to analyze the effects of time on GHQ-28, PCS and PDS. Age, gender and the baseline data for each dependent measure was entered into each ANOVA (but not Friedman s) analysis as a covariate. For ease of interpretation, results are presented using non-transformed data for medians and interquartile ranges, with probability estimates taken from analyses using transformed data. Where there was a significant difference over time, post hoc tests of simple effects were performed to determine where these differences occurred. When the Friedman test was significant, multiple Wilcoxon matched-pairs signed-rank tests were performed. Significance levels for all tests were set at 0.05 with Bonferroni adjustments used where appropriate Results Participants This study investigated 53 consecutive individuals (36 female, 17 male; mean age = / (SD) years) who underwent cervical RFN. The median [range] duration of symptoms post whiplash at entry to the study was 43 [9 195] months. Seven individuals failed to complete the study (one pregnancy; one with subsequent traumatic injuries and five lost to follow up). Four individuals continued to have ongoing pain relief (of greater than 2 years following RFN) and did not attend t3 and were excluded from the study. The median time for relief [interquartile range] of pain was 10 [7,15] months

136 At the final assessment, following the return of pain, the following medication usage was reported: anti-inflammatory medication (36%); simple over-the-counter analgesics (26%); narcotic medications (29%); anti-convulsants (12%); selective serotonin reuptake inhibitors (10%); various tri-cyclic antidepressants (7%), and selective norepinephrine reuptake inhibitors (7%) Disability Repeated measures ANOVA revealed a significant difference over time for NDI scores (F 2,144 =42.7, p<0.0001; table 6.1). Post-hoc tests demonstrated an increase in selfreported disability measured following the return of pain (from t2 to t3; p<0.0001); with no differences measured when comparing NDI scores at the return of pain to the time period prior to receiving RFN (from t1 to t3; p=1.00). Time Period NDI GHQ-28 PCS PDS (%) Score Score % met criteria Severity Score Mean (SD) [IQR] [IQR] probable PTSD [IQR] t % 9 (15) [20,34] [7,22] [2,12] t % 6 (15) [14,24] [3,16] [2,12] t % 5 (16) [16,32] [5,28] [2,12] Table 6.1: Disability and Psychological Scores over time Legend: NDI = Neck Disability Index; GHQ = General Health Questionnaire; PCS = Pain Catastrophization Scale; PDS = Post Traumatic Stress Diagnostic Scale; t1 = time-point 1 (prior to receiving radiofrequency neurotomy); t2 = (one to three months post-radiofrequency neurotomy); t3 = time-point 3 (within one-month of pain returning)

137 6.1.8 Questionnaires General Health Questionnaire (GHQ-28): The median GHQ-28 scores [interquartile ranges] are presented in Table 6.1. There was a significant effect over time for GHQ-28 scores ( 2 = 23.2,2 d.f., p<0.0001). GHQ-28 scores increased following the return of pain (t3) (Z = -3.15, p=0.0017); with no difference between t3 and t1 (Z = 1.50, p=0.13). At t3 (return of pain), the median GHQ-28 score increased from 19 (t2) to 24, indicating generalized psychological distress Pain Catastrophization (PCS): The median scores [interquartile ranges] for PCS, are presented in Table 6.1. There was a significant effect over time for PCS scores ( 2 = 13.8,2 d.f., p=0.001; Table 6.1). PCS scores were higher at t3 (return of pain) when compared to t2 (following RFN) (Z = -2.60, p=0.0094). Scores at t3 were no different from those at t1 (prior to RFN: p=0.61) Post Traumatic Stress (PDS): The median scores, interquartile ranges and proportion of participants exceeding the threshold score for probable diagnosis of Post-Traumatic Stress Disorder [406], are presented in Table 6.1. There was no difference in the proportion of individuals with a probable diagnosis of post traumatic stress disorder ( 2 = 4.42,2 d.f., p=0.11; Table 6.1); severity of post traumatic stress symptoms ( 2 = 2.39,2 d.f., p=0.30; Table 6.1); or number of post traumatic stress symptoms reported by the participants ( 2 = 0.73,2 d.f., p=0.70) at any time point Physical Measures Nociceptive Flexion Reflex (NFR): There was a significant effect of time for NFR thresholds (F 2,143 =17.8, p<0.0001). NFR threshold (Median, [Interquartile Range]) was decreased at the return of pain (t3: 8 [4,16]) compared to post-rfn (t2: 19 [13,31]; p<0.0001). At t3, the NFR threshold was lower when compared to t1 (12 [8,16]; p=0.021)

138 Thermal Pain Thresholds (TPTs): Repeated measures ANOVA revealed a significant difference over time for both CPT and HPT (both p<0.0001; Figure 6.1). Cold pain thresholds decreased between t2 and t3 (p=0.031). There was no difference in HPT between t2 and t3 (p=0.11) but an increase in HPT between t1 and t2, following RFN (p=0.002). No differences in any thermal pain thresholds were measured between t1 and t3 (p>0.24). The mean CPT following return of pain was 17.9 C, compared to 11.7 C following RFN. HPT reduced from 46.2 C (post-rfn) to 45.2 C (upon return of pain). Fig. 6.1: Thermal pain thresholds (means and SEM) over time Legend: C = degrees Celsius; HPT = Heat Pain Threshold; CPT = Cold Pain Threshold; SEM = Standard Error of the Mean; t(1) = time-point 1 (prior to receiving radiofrequency neurotomy); t(2) = (one to three months postradiofrequency neurotomy); t(3) = time-point 3 (within one-month of pain returning) Pressure Pain Thresholds (PPTs): There was a significant difference over time for PPTs at all test sites (all p<0.0001; Figure 6.2). PPTs increased at all sites between t1 and t2 (p 0.005). There were no differences between t2 and t3 (return of pain: p>0.054), although there was a trend for increased PPT over the median nerve (p=0.054) between the t2 and t3 time points. There were no differences in PPTs prior to undergoing RFN (t1) and return of pain (t3: p>0.22)

139 Fig. 6.2: Pressure pain thresholds (means and SEM) over time Legend: kpa = kilopascals; M.N. = Median Nerve; Cx = Cervical Spine; Tib. Ant. = Tibialis Anterior; SEM = Standard Error of the Mean; t(1) = time-point 1 (prior to receiving radiofrequency neurotomy); t(2) = (one to three months post-radiofrequency neurotomy); t(3) = time-point 3 (within one-month of pain returning) Brachial Plexus Provocation Test (BPPT): There were significant differences over time for elbow extension ROM with the BPPT (F 2,135 =56.4, p<0.0001). There was a reduction in elbow ROM (median [interquartile range]) between t2 (11 [6,19]) and t3 (28 [30,35]; p<0.0001), but no difference between t1 (30 [21,38]) and t3 (p=1.00) Range of Motion (ROM): Repeated measures ANOVA revealed a significant effect of time for ROM (F 2,144 = 90.8, p<0.0001; Figure 6.3). Cervical ROM decreased between t2 (post RFN) and t3 (return of pain) (p<0.0001). There was no difference between t1 (prior to RFN) and t3 (p=0.11)

140 Figure 6.3: Total (Flexion, Extension and Rotation) ROM (means and SE) over time Legend: ROM = Degrees of Cervical Range of Motion; RFN = radiofrequency neurotomy; t1 = time-point 1 (prior to receiving radiofrequency neurotomy); t2 = (one to three months post-radiofrequency neurotomy); t3 = time-point 3 (within one-month of pain returning) Cranio-cervical Flexion Test (CCFT): There was a significant main effect of time for EMG at 22mmHg (F 2,144 =3.29;p=0.042), 26mmHg (F 2,144 =5.86;p=0.0041) and 28mmHg (F 2,144 =4.84;p=0.01) levels of the CCFT but not at 24mmHg and 30mmHg levels of the CCFT (p>0.08). Post-hoc tests of simple effects were not significant at any level (all p>0.07). Thus, a general trend for reduced EMG was evident at the 22mmHg, 26mmHg and 28mmHg levels of the CCFT following RFN (t2), with another trend evident for increased EMG following the return of pain (Figure 6.4)

141 Figure 6.4: Cranio-Cervical Flexion Test RMS values (medians) over time Legend: mmhg = millimetres mercury; RMS = Root Mean Square Discussion This study demonstrated that the majority of physical and psychological features of chronic WAD deteriorate within one month of the return of pain following RFN to the cervical facet joints. The measures returned to levels that were no different to those demonstrated prior to RFN being performed. As we have previously shown that these factors improve following pain relief with RFN [400,413]; the deterioration of results with the return of pain indicates dynamic modulation of the processes underlying these measures with manipulation of cervical facet joint nociception. To our knowledge, apart from one study that demonstrated increased psychological distress [225]; no previous study has investigated changes in a wider range of physical and psychological manifestations of chronic WAD after the effects of RFN have dissipated and pain has returned. Participants reported significant reduction of their neck pain for approximately 10 months following the cervical RFN. This is consistent with other cohorts undergoing cervical RFN [61,283,326,328,407] and thus we are confident that our sample is representative of patients receiving this form of intervention. The eventual return of pain following RFN is generally thought to be as a result of the return of nociception following regeneration of the

142 medial branch of the dorsal ramus [332], and is supported by data demonstrating that successful pain reduction occurs with repeat RFN [283]. However, we cannot be completely certain that return of pain in individuals in our study reflects the return of nociception, given that transduction of nociception is not necessary to result in the perception of pain [36]. Participants reported similar levels of disability within one month of the return of pain to those prior to undergoing RFN. Reported medication intake increased and was similar to pre-rfn levels [376]. Psychophysical measures of central hyperexcitability (cold pain thresholds, NFR threshold and responses to the BPPT) deteriorated within one month of the return of pain indicating a plasticity of central nociceptive processing based on modulation of peripheral nociception. We previously demonstrated an immediate and sustained improvement in CPT, BPPT and NFR threshold, of moderate to large effects following RFN [400]. The proposal that the central hyperexcitability arises as a result of ongoing peripheral nociception is further supported by, amongst others, the significant deterioration in these thresholds observed within one month of return of pain. This role of peripheral nociception has also been proposed from results of other studies in individuals with persistent WAD [32,274,339]. There was a different temporal relationship for PPT measures compared to the CPTs and NFR thresholds. Whereas the CPTs and NFR showed a significant increase in sensitivity following the return of pain, PPTs did not decrease significantly, although there was a trend in this direction. This may suggest that different mechanisms underlie NFR excitability and cold hyperalgesia compared to widespread mechanical hyperalgesia [161]. Pressure pain thresholds have been shown to be a sensitive measure to detect endogenous pain inhibitory mechanisms [415], and as such, changes in PPT may be more reflective of inhibitory processes [415]. Spinal cord hyperexcitability measured with the NFR and cold hyperalgesia may reflect excitatory processes arising from the increased peripheral nociception [416]. Thus, these results may indicate that appropriate inhibitory processes have not developed within this time period following the return of pain, in comparison to the excitatory measures evident. It is also possible that widespread hypersensitivity to pressure may take longer to deteriorate following return of pain, than the one month period that was utilized in our study. Findings of a recent study suggested that deficiencies in conditioned pain modulation (CPM)

143 relate more to the duration of pain than the presence of pain itself [417]. It would seem that the inclusion of measures of CPM may shed more light on these proposals. Thermal hyperalgesia was also evident within one month of the return of pain, although HPTs were not significantly different to those during pain relief (although HPT findings are generally found to be variable [35,146,168]). Cold pain thresholds improved following RFN and worsened upon return of pain suggesting that peripheral mechanisms contribute to the presence of cold hyperalgesia. There is data indicating that cold hyperalgesia may reflect sensitized afferent fibres [388] and/or insular cortex dysfunction [389]. In WAD, cold hyperalgesia has also been shown to be associated with psychological factors including posttraumatic stress symptoms [65] and pain catastrophizing [63]. In our study, both heat and cold hyperalgesia worsened upon return of pain. Thus, it may be that the increase in thermal hyperalgesia following return of pain is suggestive of deterioration in underlying central mechanisms. Ongoing restriction in cervical ROM is common in patients with chronic WAD [38,64]. We previously demonstrated that ROM improved immediately following cervical RFN, indicating that peripheral nociceptive input from the cervical facet joints may contribute to this movement loss [400]. The results of this study would support this proposal, as ROM significantly decreased again following the return of pain. An alternative explanation could include heightened fear of movement upon the return of pain, which has previously been documented [418]. Future studies may wish to investigate the role of fear in conjunction with peripheral nociception to clarify this relationship further. Cervical motor control as measured with the CCFT did not significantly improve following RFN [400], or worsen after return of pain. There was a trend towards improvement following RFN and upon return of pain, at certain levels of this test (22, 26 and 28mmHg). These results suggest that pain has little effect on cervical motor control. Previous research has also shown that motor control deficits remain even after the resolution of pain [64]. Consequently, this led some authors to advocate re-training for restoration of effective cervical neuromotor control and perhaps the prevention of pain recurrence [175,318], although the benefits of this approach remain unknown. The return of pain was also associated with increased psychological distress and pain catastrophization. Return of distress following return of pain has previously been reported [225]. In conjunction, these findings indicate that modulation of pain also modulates levels of

144 distress and pain catastrophizing. However there was no temporal relationship between pain and PTSD symptoms. This may be a result of the study sample size, or that PTSD symptoms are not as dependent on pain as other psychological substrates. Jenewein [397] demonstrated that chronic PTSD symptoms impact pain levels, but not vice versa. Otis et al. [240] reviewed models explaining the relationship between chronic pain and PTSD, with many models demonstrating that factors, such as fear, avoidance, anxiety sensitivity, and catastrophizing, co-exist for the maintenance of both conditions. Hence, factors other than, or in addition to pain, may be required for PTSD symptoms to be triggered or alleviated. The study has limitations. Due to its clinical context, measurements were performed by an unblinded assessor. However, the study aims were not conveyed to participants until after study completion. The results apply to individuals with a localized peripheral source of nociception who undergo RFN after successful comparative blockade and may not be applicable to the wider WAD population. Additionally, individuals returned for laboratory evaluation within one month return of pain, and we cannot be sure that this reflects return of peripheral nociception or that pain is due to other unknown reasons that developed. Nevertheless, we can be fairly confident that peripheral mechanisms contribute to the experience of pain and clinical manifestations of patients with chronic WAD. Our initial study demonstrated that after a stable baseline 12 month period, all physical measures (except muscle activity with CCFT) improved following reduction of nociception and concurrent reduction in pain and disability [400]. In addition, apart from PTSD, psychological manifestations demonstrated improvement following RFN [413]. This present study demonstrates complementary findings. Upon return of pain there is a worsening in both physical and psychological manifestations, with these measures no longer being any different to baseline (prior to RFN). Thus, in individuals with chronic WAD, consideration should be given to investigate peripheral sources of nociception where possible

145 CHAPTER 7 The previous studies have demonstrated that individuals with chronic WAD presenting with nociception arising from the cervical facet joint(s) have a complex array of clinical manifestations that are successfully modulated with RFN (apart from posttraumatic stress symptoms). We have also demonstrated that the clinical features deteriorate upon the dissipation of the effects of the RFN. However, what is still uncertain is whether any of these features predict success of RFN? The aim of this final study was as follows: 1. To determine if clinical features (pain, disability, psychophysical sensory measures and psychological measures) predict a successful response (Global Rate of Change measure 4) to cervical RFN. Publication: Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling M. Low Pain Catastrophization and Disability Predicts Successful Outcome to Radiofrequency Neurotomy in Individuals with Chronic Whiplash (Accepted for Publication: Pain Practice. Nov 2, 2014)

146 7.1 Study 5 Low Pain Catastrophization and Disability Predicts Successful Outcome to Radiofrequency Neurotomy in Individuals with Chronic Whiplash Abstract Objectives: Physical and psychological symptoms of individuals with chronic whiplash associated disorders (WAD) are modulated by successful treatment with cervical radiofrequency neurotomy (RFN). However, not all individuals respond to cervical RFN and it is unknown which clinical features predict successful response to cervical RFN. Methods: This prospective cohort study investigated 53 individuals with chronic WAD (36 female, 17 male; mean age = / (SD) years) who underwent cervical RFN. Predictor variables measured at baseline (Prior to RFN) included self-reported pain (VAS), disability (NDI), posttraumatic stress symptoms (PDS), pain catastrophizing (PCS) and measures of sensory hypersensitivity (pressure and cold pain thresholds). The outcome measure was perceived Global Rating of Change (where scores 4 were classified as a successful response) 3-months post-cervical RFN. Results: Univariate logistic regression demonstrated that disability and pain castrophizing were associated with successful response of cervical RFN (both p < 0.05). Multivariable logistic regression demonstrated that low levels of pain catastrophizing and disability remained significant predictors of a successful response to cervical RFN (both p < 0.05). Conclusions: Low levels of pain catastrophizing and disability independently predicted a successful response to cervical RFN in patients with chronic WAD

147 7.1.2 Introduction Individuals with chronic whiplash associated disorders (WAD) present with complex clinical manifestations, characterized by central nervous system hyperexcitability [63,154], motor [180] and sensori-motor system dysfunction [189,200], together with psychological features including posttraumatic stress symptoms, distress, anxiety and depression [8]. Various conservative treatments have been trialled for chronic WAD, incorporating physical (such as exercise), psychological (e.g. cognitive behavioural therapy) or combined approaches. Unfortunately, conservative treatment has failed to substantially reduce pain and disability in patients with chronic WAD [186,187,319]. Cervical radiofrequency neurotomy (crfn) is the only treatment for chronic WAD shown to demonstrate clinically relevant reductions in pain in patients with pain arising from the facet joints [61,225,340]. However, not all individuals respond to this procedure [27]. One study investigated various features (including demographics, radiological, pharmacological and physical examination findings) that may influence success of cervical RFN [303]. The only clinical variable associated with success was paraspinal tenderness [303]. However in this study, determination for proceeding to cervical RFN was based on positive response (at least 50% pain relief) to a single diagnostic medial branch block (MBB) for the putative facet joint. As single blocks have been associated with high false positive rates of cervical facet joint pain [58,419,420], there is a possibility of low response or failure of cervical RFN when performed using this selection criteria [358] and this may have influenced the results. Thus it is not clear who will or will not respond to cervical RFN, but in view of the myriad of physical and psychological factors present in patients with chronic WAD, it would be logical to explore their potential to predict responsiveness to this procedure. It is feasible that some of the physical and psychological manifestations of chronic WAD may predict responsiveness to cervical RFN, but this is yet to be investigated [376]. For example, individuals with features indicative of central sensitization demonstrate poor response to surgery [350], whilst the absence of central sensitization predicted an improved response to physiotherapy in individuals with carpal tunnel symptoms [349]. The presence of both mechanical (reduced pressure pain thresholds) and cold hyperalgesia (elevated cold pain thresholds) in individuals with chronic WAD (which is thought to be indicative of the presence of central sensitization [362]) has been shown to be associated with poor response to

148 conservative physiotherapy [186]. Pain catastrophizing is associated with enhanced pain reports, disability [247,248], poor prognosis [398], lower pain threshold/tolerance levels [63] and with poor response to diagnostic facet joint injections [376] in individuals with WAD; whilst posttraumatic stress symptoms (present in approximately 20-30% of individuals with chronic WAD) also predict poor health outcomes in chronic WAD [228,230,231,421]. High levels of pre-procedural pain have also been associated with poor responsiveness to neurotomy involving the sacro-iliac joint [422]. The aim of this study was to determine if pain, disability, psychophysical sensory measures and psychological features predicted response to cervical RFN in individuals with chronic WAD Materials and Methods Design: A prospective cohort study design was employed and conducted at a tertiary spinal intervention centre in Calgary, Alberta, Canada. Participants were assessed at the following time points: one month prior to receiving cervical RFN, and 1 and 3 months post-cervical RFN. The primary end point was 3 months Participants: Inclusion and Exclusion Criteria: These criteria did not differ from studies 2 and 3 and are documented under sections and on pages 96 and 114 respectively Instrumentation: Pressure Pain Thresholds Pressure pain thresholds (PPTs) were measured using a pressure algometer (Somedic AB, Farsta, Sweden), bilaterally over two pairs of homologous anatomical sites (putative facet joint pillars (as a measure of local hyperalgesia) and upper one third of the muscle belly of tibialis anterior (as a measure of remote sensory hypersensitivity)) [376]. Triplicate recordings were taken at each site and the mean value for each site used in the analysis. Cold Pain Thresholds

149 Cold pain thresholds were measured bilaterally over the cervical spine using the TSA II Neurosensory Analyzer (Medoc Advanced Medical Systems; Minneapolis, MN, USA) [376]. Three recordings were taken at each site and the mean value for each site used in the analyses. A full description of these tests is provided in Appendix 1. Questionnaires: Individuals completed a standard intake questionnaire (as previously reported) which provided standard demographic, crash-related information, symptom profile and pharmacological intake [376]. Following cervical RFN, individuals were asked to rate the success of the procedure via a 15-point Global Rating of Change (GROC) scale. The GROC is a 15-point global rating scale ranging from -7 ( a very great deal worse ) to 0 ( about the same ) to +7 ( a very great deal better ) [423]. Intermittent descriptors of worsening and improving are assigned values from -1 to -6 and from +1 to +6, respectively [424,425]. Scores of +4 and +5 are indicative of moderate changes in a person s status and that scores of +6 and +7 indicate large changes in a person s status [423]. Participants who rated their perceived recovery on the GROC as a very great deal better, a great deal better, a good deal better, or moderately better (i.e. a score of +4 or greater) would be considered to have experienced a successful outcome. Measures of pain (visual analogue scale VAS) and disability (Neck Disability Index NDI, [353]) were also collected as per Appendix 1. Pain and disability measures were chosen as predictors of poor response to cervical RFN, as they are robust predictors of poor prognosis in individuals with WAD [6], together with knowledge that pre-procedural pain has previously predicted failure of sacro-iliac joint radiofrequency denervation [422]. The Posttraumatic Diagnostic Scale (PDS) [356] assessed the severity of posttraumatic stress symptoms (in relation to the MVC that resulted in their WAD injury). The symptom severity score was calculated by summing the participant s responses to the 17 symptom items. The cut-offs for symptom severity rating are 0 no rating, 1 10 mild, moderate, moderate to severe and >36 severe. This measure was chosen, as a recent study suggested subgrouping was recommended based on presence of such features [228]. The Pain Catastrophizing Scale (PCS) [245] was used to measure pain catastrophization [376,413]. Pain catastrophizing (utilizing the PCS [245]) has been

150 associated with a poor response to diagnostic facet joint injections [376]. A total score was calculated by summing the responses to the 13 individual items, with a 5-point rating scale ranging from (0) not at all to (4) all the time. Participants first completed all questionnaires, after which a standard protocol was used for the order of tests [184]. The same examiner performed all physical tests. For a full description of these questionnaires, including detailed scoring criteria and appropriate clinimetrics, please refer to Appendix Procedure: The initial diagnostic work-up (Chapter 4.1.4), RFN procedure (Appendix 2) and study procedure (Chapter ) has been reported [376,400] Data Analysis Descriptive statistics were utilised for baseline group (SUCCESS vs. less SUCCESS) characteristics (including demographics age, gender and duration of symptoms) prior to and following cervical RFN. The distribution of categorical variables (gender) in each group was compared using Pearson s 2. Continuous variables were compared with independent t-tests, and Mann-Whitney U test was used for non-parametric data (duration of symptoms, PCS and PDS). The clinical measures were analyzed for their association with the dependent outcome variable (SUCCESS = GROC 4) at the three-month assessment following cervical RFN via univariate and multivariate logistic regression. In univariate logistic regression, the independent variables were pressure pain thresholds (local and remote), cold pain thresholds, PCS scores and PDS symptom severity scores. Univariate analyses were performed to determine which predictor variables to include in the multivariable model. The level of significance for inclusion in the multivariable model was p 0.2. Variables retained in the multivariable model were screened for collinearity by calculating bivariable Spearman correlation coefficients. Variables with a significant relationship (p < 0.05) were not used together in the regression model. For multivariable logistic regression, a stepwise forward approach was utilized. A Receiver Operating Curve (ROC) analysis to determine the discriminative ability of the model was performed. The sensitivity and specificity of this

151 model in predicting SUCCESS was also calculated via the ROC analysis. Assumptions of normality, nonmulticollinearity, and homoscedasticity were tested through examination of histograms, correlation matrices, and a plot of predicted to residual regression values, respectively. Data were log transformed, where required to ensure normality. All data were analyzed with Stata 9.0 statistical software Results Participants: Fifty-four individuals received cervical RFN. As previously reported [400] the most common facet joint involvement was C2/3 (41%), with C5/6 and C6/7 implicated in 25-30% of participants. Approximately 30% of participants had bilateral injections. One individual sustained neuritis (this was the only side effect noted for the duration of the study), and was excluded from the study. Thus, 53 individuals (36 female, 17 male; mean age = / (SD) years) formed the study group. Two individuals attended follow-up 1 month following cervical RFN, and then were lost to follow-up. Both individuals reported that they had not perceived any benefit from cervical RFN with no relief of pain reported (GROC = 0). One individual attended at the 3-month period reporting that she was pregnant. The duration of her relief of pain was documented to be 3-months. All other individuals attended review appointments, both at 1- and 3-months post-cervical RFN. Apart from the 3 individuals lost to follow-up (whose 1-month GROC data was carried forward), all data was used from the 3- month primary end point of the study. As has been previously reported, at the time of receiving the initial cervical facet joint diagnostic injection, the median [range] duration of symptoms post whiplash injury was 43 [9 195] months [376]. Following the initial diagnostic facet joint blockade, there was a mean (+/-SD) wait of 10.4 (+/-4.5) months until cervical RFN was performed [400]. All participants reported receiving initial conservative treatment following the MVC consisting of any of the following: physiotherapy, chiropractic and/or massage therapy [376]. Thirty-one participants were receiving conservative treatment at time of participation in the study. Twenty-six participants had previously attended the local health authority multi-disciplinary chronic pain centre

152 Fifty three percent were involved in ongoing compensation claims; other regional musculoskeletal symptoms were noted in 57% of individuals (i.e. headaches (44%); low back pain (34%), thoracic spine pain (21%), shoulder/arm pain (21%) and jaw (8%)); 51% were university educated; 77% had full employment for the duration of the study, and 74% reported that they were in a co-habitative relationship. Participants Classification at 3 months Post-Cervical RFN Forty individuals (75%) reported a successful (GROC 4) outcome at the 3-month period following cervical RFN. Nine individuals (17%) reported a GROC score of between 0 to 3 (almost the same, a little bit better or somewhat better); whilst 4 individuals (8%) reported a score of 0 (no change), which included the two individuals lost to follow up (whose GROC scores were carried forward from the 1-month time period). Pre-Cervical RFN Group Differences at Baseline There was no significant difference in age or gender distributions, pain (VAS) or duration of symptoms between the SUCCESS (GROC 4) and less SUCCESSFUL groups at baseline prior to cervical RFN being performed (Table 7.1). There was also no significant difference between groups for compensation status, education levels, employment status, marriage status, or utilization of prior treatment status (all p>0.22). Individuals in the SUCCESS group reported less disability (NDI) and pain catastrophizing (PCS) prior to receiving cervical RFN. Table 7.2 demonstrates the changes in outcome measures over time for both groups

153 Group SUCCESS (n=40) Less SUCCESS (n=13) P value Mean (+/- SD) or Median [IQR] Gender 28/12 8/ (F/M) Age 45.4 (11.1) 42.7 (10.1) 0.45 (yrs) Duration of Symptoms 41 [30,65] 44 [42,178] 0.25 (mths) Pain 54 (21) 61 (15) 0.26 (VAS) Disability 40 (14) 51 (18) 0.03 (NDI) Pain Catastrophizing 13 [6,22] 19 [17,31] 0.02 (PCS) Posttraumatic Stress 7 [2,14] 14 [3,14] 0.39 Symptom Severity (PDS) Cervical PPT 203 [153, 250] 157 [118, 264] 0.32 (kpa) Tib Ant PPT 360 [312,426] 329 [252,520] 0.91 (kpa) Cold Pain Threshold ( C) 16.6 (9.2) 19.7 (2.7) 0.30 Table 7.1: Patient characteristics by group status prior to cervical RFN Legend: VAS = Visual Analogue Scale; NDI = Neck Disability Index; PCS = Pain Catastrophizing Scale; PDS = Posttraumatic Stress Diagnostic Scale; PPT = Pressure Pain Threshold; kpa = kilopascal; Cx = Cervical Spine; Tib Ant = Tibialis Anterior; t2 = one-month prior to RFN; SD = Standard Deviation; IQR = Interquartile Range; Bolded = p <

154 Pre-cRFN 1 Month Post-cRFN 3 Months Post-cRFN Pain (VAS /100mm) SUCCESS 54 (21) 19 (16) 19 (19) Less Success 61 (15) 45 (21) 44 (18) Disability (NDI %) SUCCESS 40 (14) 25 (14) 23 (15) Less Success 51 (18) 41 (18) 41 (13) PCS (/52) SUCCESS 13 [6,22] 8 [3,15] 4 [0,11] Less Success 19 [17,31] 18 [14,33] 16 [14,33] PDS (/51) SUCCESS 7 [2,14] 5 [0,12] 4 [2,10] Less Success 14 [3,14] 9 [6,18] 6 [2,29] PPT Cx (kpa) SUCCESS 203 [153,250] 258 [198,319] 299 [230,370] Less Success 157 [118,264] 190 [148, 239] 203 [169,308] PPT Tib Ant (kpa) SUCCESS 360 [312,426] 429 [366,551] 524 [397,657] Less Success 329 [252,520] 396 [301,492] 369 [333,736] CPT ( C) SUCCESS 19.7 (9.9) 14.1 (9.9) 13.7 (9.0) Less Success 16.6 (9.2) 11.7 (8.6) 10.2 (8.6) Table 7.2: Group differences vs. time prior to and following cervical radiofrequency neurotomy (RFN) Legend: crfn: Cervical Radiofrequency Neurotomy; VAS: Visual Analogue Scale; NDI: Neck Disability Index; PCS: Pain Catastrophization Scale; PDS: Posttraumatic Diagnostic Scale; PPT: Pressure Pain Threshold; Cx: Cervical; Tib Ant: Tibialis Anterior; CPT: Cold Pain Threshold Success: GROC (Global Rating of Change) 4 at 3-months post-rfn; Less Success: GROC<

155 Prediction of Cervical RFN SUCCESS 3 Months Post-Cervical RFN: Table 7.3 presents the results of the univariate logistic regression analyses. In predicting SUCCESS of cervical RFN, the following variables were statistically significant: disability (NDI) and pain catastrophizing (PCS). The other four variables under investigation demonstrated wide 95% confidence intervals and were not significant predictors of SUCCESS. Clinical Variable Odds Ratio Standard Error Probability (95% CI) Pain ( ) Disability ( ) PCS ( ) PDS symptom severity ( ) LogPPTCx ( ) LogPPTtibant ( ) Cold Hyperalgesia 0.96 ( ) Table 7.3: Odds ratios of the clinical variables in univariate logistic regression for predicting cervical RFN SUCCESS Legend: CI = Confidence Interval; PCS = Pain Catastrophizing Scale; PDS = Posttraumatic Stress Diagnostic Scale; PPTCx = Pressure Pain Threshold in the Cervical Spine; PPTtibant = Pressure Pain Threshold over Tibialis Anterior; Bolded = p <

156 Correlation between Predictor Variables: To ascertain whether the variables that demonstrated significance in univariate regression were related, a correlational analysis was conducted between predictors that demonstrated a relationship (p 0.2) with cervical RFN SUCCESS (PCS, PDS Severity and NDI). Other variables (VAS, LogPPTCx, LogPPTtibant and Cold Pain Thresholds) were discarded from analysis. There was a significant correlation between disability and pain catastrophization or post traumatic stress severity (r = 0.56, p < ), albeit moderate in strength, with a strong and significant correlation between pain catastrophization and post traumatic stress severity (r = 0.77, p < ). Due to the correlation between predictor variables, multivariable analyses were performed. Multivariable logistic regression models were constructed utilizing the predictor variable NDI. A second model utilized PCS as the predictor variable. Models utilizing PDS Severity were also constructed, but did not reach significance. Following a forwards stepwise approach, two models reached statistical significance in predicting SUCCESS of cervical RFN at 3 months (Table 7.4). The first model included the single variable: NDI (LR chi2(1) = 4.80, p=0.029). The second model included the single variable: PCS (LR chi2(1) = 6.36, p=0.010). For model 1, ROC analysis resulted in an AUC of 0.68 and correctly predicted 98% of those with a successful outcome (sensitivity), but only 23% of those with a less successful outcome (specificity) with an overall success rate of 79% (Table 7.4). For model 2, ROC analysis resulted in an AUC of 0.73 and correctly predicted 95% of those with a successful outcome (sensitivity), and 23% of those with a less successful outcome (specificity) with an overall success rate of 77% (Table 7.4)

157 Model Predictor Variable #1 NDI #2 PCS Odds Ratio (95% CI) 0.91 ( ) 0.94 ( ) Standard Error Probability Sensitivity Specificity Table 7.4: Accuracy statistics with 95% confidence intervals for the two models predicting success of cervical RFN at 3 months Legend: NDI = Neck Disability Index; PCS = Pain Catastrophizing Scale; CI = Confidence Interval Discussion The results of this study were in agreement with previous research investigating cervical RFN, whereby approximately 75% of individuals successfully responded and reported ongoing success 3-months following the procedure [61,326,328,340]. Low levels of pain catastrophization and disability were found to predict success of cervical RFN, whereas various physical (pain levels, local and remote pressure pain thresholds and cold pain thresholds) and psychological features (pain catastrophization and posttraumatic stress symptoms) did not predict a successful (or less successful) response to cervical RFN. We have previously demonstrated that cervical RFN improves physical (decreases central hyperexcitability and increases neck movement) and psychological manifestations (psychological distress and pain catastrophizing) of chronic WAD [400,413]. However, as not all individuals respond to cervical RFN, our previous study results may not have highlighted differential inter-individual treatment responses [323]. We hypothesised that individuals with less complex clinical features would respond better to cervical RFN. This was not the case. Our findings contrast with those of Cohen and colleagues [303] as we found that midline tenderness (local cervical PPTs) was not associated with a successful response to cervical RFN. However there are differences between the studies. Cohen and colleagues used a dichotomised measure of neck midline tenderness (pain overlying the facet joints with an estimated 4 kg of manually applied force), whereas we used a continuous variable of ratecontrolled algometry measuring pain thresholds over the neck. They also used a retrospective

158 study design and this may have influenced the selection criteria of individuals investigated and possibly resulted in differential bias of results [303]. Additionally the selection criteria to determine suitability to undergo cervical RFN were different between the studies, with Cohen et al using a positive response to single medial branch block compared to our comparative double facet joint injection procedure. This may have resulted in a less successful response to cervical RFN in Cohen et al s study due to the high rate of false positives encountered with a single block procedure prior to RFN [58]. Additionally, the outcome used by Cohen et al was 6 months post injury, and ours was 3 months and this may also contribute to the different results between the two studies. Our study demonstrated that two models predicted a successful response to cervical RFN. Our finding that lower disability levels are a predictor of success for cervical RFN is not surprising. The presence of higher disability levels (NDI > 28%) in the acute stage of WAD has frequently been shown to predict poor long-term health outcomes following the injury [6,231,421,426,427], with our study demonstrating the complementary finding that lower disability is a predictor of responsiveness to cervical RFN. Our previous results also demonstrated that individuals who did not respond to initial facet joint block injections (prior to undergoing cervical RFN) presented with higher levels of pain catastrophizing [413]. Thus, the current study result is not surprising, especially when taken with other studies showing that pain catastrophizing is associated with poor prognosis [398] and enhanced pain reports with concurrent disability [247,248]. The specificity of both predictive variables (NDI and PCS) was low, indicating that there was a 77% probability of a false positive diagnosis of success being achieved with higher PCS or NDI scores. The sensitivity was high (0.95), indicating that individuals with low pain catastrophizing or disability could be predicted to have a successful response to cervical RFN. Hence, some clinical utility is evident for individuals with lower measures of pain catastrophizing (PCS < 24, [428]) and disability (NDI < 28%), with limited utility for individuals with higher scores on these measures. Thus, higher levels of pain catastrophizing or disability should not prevent an individual from benefitting from cervical RFN. We have previously demonstrated that individuals with high pain catastrophizing and disability benefit from cervical RFN [400,413]. Pain catastrophizing and disability scores were better predictors of success, in comparison to various other physical and psychological measures utilized in this study. Individuals with various other

159 clinical features (e.g. widespread pressure hyperalgesia, cold hyperalgesia or higher levels of post-traumatic stress symptoms) still demonstrated benefit from undergoing cervical RFN, and these features did not predict success or failure. Overall, apart from pain catastrophizing and disability, there was no significant clinical feature, either alone or in combination that successfully predicted success of cervical RFN, indicating that response to the initial facet joint diagnostic blockade continues to be the most suitable indicator for cervical RFN success [393]. Certain study limitations need to be mentioned. Thirty-one patients were receiving concurrent conservative treatment at the commencement of this study, and this may have confounded the results. However, given that these individuals did not report any improvement over time in the twelve months before undergoing RFN [376], this does not appear to be highly likely. A definition of recovery is challenging for individuals with chronic WAD [429]. The GROC score chosen for success in this study has been reported to be indicative of moderate to large changes in a person s status [423]. As this study contained both physical and psychological measures, it was decided that this outcome was satisfactory for the purposes of evaluation of patient s overall outcome, as it likely incorporated a combination of pain and disability relief and possibly reflected reduction of psychological manifestations all of which are important outcomes for individuals with chronic pain after a whiplash injury [430]. However, the outcome measure chosen (GROC) may have under reported the success of cervical RFN, as every individual in this study subsequently underwent repeat cervical RFN upon return of their symptoms. Another consideration with this outcome measure, is the possible lack of clear delineation between individuals with moderate success when compared to individuals who had a less successful response. This may have prevented certain predictor variables from reaching significance and would warrant evaluation in a larger study. The outcome measures also included self-report measures that may have limited diagnostic accuracy and subsequent utility within the models investigated. One must also note that the model predicting success of cervical RFN is only as good as the variables measured. Given the broad range of physical and psychological measures evident in the clinical presentation of individuals with chronic WAD [2,66], not all measures can be entered into logistic regression models, and thus, the results of this study

160 require replication in future research. Intuitively, models are also more likely to reach significance if the variable under investigation is included as a predictor. Thus, it may be that the outcome measure chosen (GROC) is closely associated with catastrophizing and disability, and if a different outcome was chosen (e.g. pain or stress ), different predictors may have been significant in predicting success. Thus, the results of this study investigating associations between multiple variables are a first step in identification of candidate variables for a prognostic model that need to be repeated in future studies in the context of a randomized controlled trial to determine the robustness, generalizability and validity of these measures as predictors of success for cervical RFN. In summary, this study demonstrated that individuals with chronic WAD respond to cervical RFN, irrespective of their clinical presentation. Low levels of catastrophizing and disability predicted a successful response to cervical RFN

161 8.1 Overview CHAPTER 8 Discussion and Conclusions Individuals with chronic whiplash associated disorders (WAD) present with a complex array of physical and psychological features including central hyperexcitability, motor dysfunction, psychological distress, pain catastrophization and posttraumatic stress symptoms [30]. Research demonstrating the ability of particular treatment regimes to successfully reduce these features in the chronic state is limited [61,186,187,431] and certain clinical features (combination mechanical and cold hyperalgesia) seem resistant to conservative care [186]. Thus, treatments or strategies that can alleviate these features and successfully reduce pain and disability would be of significant benefit for all involved. It is challenging to determine the reason(s) for the persistence of these symptoms, and in particular, if a pathoanatomical lesion is responsible for some or all of these symptoms [87]. It is made even more challenging by the inability of current diagnostic imaging to detect lesions in the cervical spine after whiplash trauma [25,432]. Even when lesions have been detected, their relevance has been questioned [123,433]. Thus, it is unclear in individuals with chronic WAD whether tissue lesions are responsible for the persistence of the various clinical features. There is also much debate as to whether the clinical manifestations are driven by an ongoing peripheral nociceptive source (the anatomical lesion) [53-55] or are self-maintaining due to neuroplastic changes in the central nervous system [36]. The cervical facet joint has been implicated in clinical research as one of the anatomical structures responsible for neck pain in individuals following whiplash injury [28]. Basic science research has also established an association between nociception in the cervical facet joints and some of the clinical features of WAD, and in particular behavioural hypersensitivity [374]. Cervical radiofrequency neurotomy (RFN) is a neuroablative technique that can be utilized to successfully treat individuals with facet joint nociception, identified via comparative medial branch blocks (MBBs) [345]. However, there has been no detailed study of the relationship between cervical facet joint nociception and the variety of clinical features demonstrated in individuals with chronic WAD. It was also unknown whether persistent cervical facet joint nociception contributes to the physical and

162 psychological features evident in individuals with chronic WAD. Likewise it was unknown whether effective modulation of this nociception through RFN improves these features. It was important to determine whether modulation of these features was possible through effective treatment of underlying nociception, as this would assist in providing validated treatment options for these individuals. These deficits in knowledge prompted this body of research. The primary aim of this thesis was to determine if the physical and psychological manifestations of chronic WAD could be effectively modulated through successful response to RFN. This, and subsidiary research questions to meet current deficits in knowledge, were answered through a series of studies. 8.2 Determination of Clinical Features of Individuals with Cervical Facet Mediated Pain Generally, inception cohorts in studies investigating clinical features in individuals with chronic WAD, utilize the Quebec Task Force grading system [2], which results in a heterogeneous whiplash patient cohort. It was important in the first instance to determine if individuals with neck pain attributed to cervical facet joint nociception were representative of the individuals classified as WAD II in these studies and whether they presented with similar clinical manifestations. Thus, two groups of individuals classified as WAD II were examined, together with a group of healthy control individuals. One WAD group had successfully responded to diagnostic facet joint injections (intra-articular facet joint injection followed by MBB) and thus were determined to have neck pain arising from cervical facet joint nociception; one group did not respond to cervical facet joint injections (non-responders) [376]. The only difference in physical and psychological clinical manifestations demonstrated between the two WAD groups involved pain catastrophization which was elevated in the non responder group [376]. Increased medication intake was also documented in the non responder group. Both WAD groups demonstrated increased central hyperexcitability, reduced neck motion and increased upper quadrant electromyography (EMG) when performing the CCFT, together with psychological distress and elevated post traumatic stress symptoms when compared to the healthy cohort of individuals [376]. It was postulated that the higher levels of pain catastrophization may have been a factor of study

163 methodology as this measure was recorded after the completion of the double facet block procedure. Individuals who did not respond may be more likely to have negative thoughts about their pain related disability. Alternatively, the presence of pain catastrophization might have been evident prior to the procedures and in itself been responsible for the poor outcomes [245,351]. Future studies need to prospectively investigate any relationship between pain catastrophization and interventional outcomes. In summary, this study demonstrated that the individuals proceeding to RFN presented with similar clinical manifestations to those previously documented in the literature. In particular, the cohort had features that were associated with poor prognosis [6,231] and resistant to improvement with various conservative treatment regimes [186,187]. 8.3 Physical Manifestations of Chronic WAD Are Modulated by Cervical RFN Study 2 investigated the group of individuals who proceeded to cervical RFN following their successful response to the double facet block procedures [400]. There was a significant wait time between completing the facet blocks and receiving the cervical RFN. Thus it was possible to investigate whether the physical features (central hyperexcitability, neck motion and CCFT performance) were stable or changed with time. It was found that no features significantly improved or worsened over the 10 month time period, indicating the stability of this group s chronic condition in the pre-intervention period [400]. Following the cervical RFN, individuals were followed-up on two occasions one, and three-months postcervical RFN. Importantly, it was found that following cervical RFN, pain and disability reduced and, with the exception of muscle function (CCFT), measures of central hyperexcitability (pressure pain thresholds (PPTs), heat and cold hyperalgesia, nociceptive flexion reflex (NFR) thresholds and elbow extension range of motion (ROM) during the brachial plexus provocation test (BPPT)) all improved and were no different from those of a healthy cohort of individuals [400]. The improvements were maintained at the 3-month follow-up. These findings suggested that peripheral nociception was responsible for modulating the physical features of this cohort with chronic WAD, and that these improvements occur within a short time period post-cervical RFN. Of particular interest, was the finding that peripheral nociception modulated central hyperexcitability. It seems that the

164 presence of a peripheral lesion may be driving the persistent hyperexcitability of the central nervous system (CNS), and modulation of central mechanisms is possible, and occurs in a short time period. This contrasts with alternative views which contend that initial neuroplastic changes in the CNS are independent of peripheral involvement, are possibly self-generating and are likely to require central input to produce change [36]. Thus the research in this thesis has produced a key finding namely, the importance of effectively treating peripheral tissue lesions in individuals in chronic WAD to improve physical manifestations. 8.4 Psychological Manifestations of Chronic WAD Are Modulated by Cervical RFN In study 3, investigations focussed on whether the psychological manifestations (psychological distress, pain catastrophization and posttraumatic stress symptoms) of chronic WAD could be effectively modulated with cervical RFN. In tandem with the physical measures, there was no change in psychological manifestations during the 11 months between diagnostic facet blocks and cervical RFN. Following cervical RFN, individuals reported statistically significant and clinically relevant (large effect sizes) improvement in psychological distress and pain catastrophizing, but not in posttraumatic stress symptoms. The improvements in pain catastrophizing and psychological distress were apparent within one month of the cervical RFN and were sustained at the three month follow up, which mirrored the improvements in pain and disability measures. These results indicate the likely association between psychological measures and pain levels. In contrast, the lack of significant improvement in posttraumatic stress symptoms suggests that these symptoms are independent of pain levels, but may explain the residual psychological distress (33%) demonstrated post-rfn. This supports previous research by Jenewein [397], who found that posttraumatic stress symptoms influenced pain measures in the chronic stage of recovery following trauma, but the converse did not apply. Given that some improvement in symptomatology was noted in this group, a lack of power may have also contributed to this finding. Of particular note, there was substantially greater improvements in the psychological measures following cervical RFN than achieved when these psychological manifestations were targeted with psychosocial interventions [250]

165 8.5 Physical and Psychological Manifestations Deteriorate On Return of Pain Studies 2 and 3 made apparent that reduced nociception (and associated pain) following cervical RFN resulted in improvements in physical and psychological manifestations of chronic WAD. However, pain reduction associated with cervical RFN is finite [283] and individuals reported that their pain returned approximately 10 months postcervical RFN, which is consistent with literature reports. As predicted, upon return of pain, participants demonstrated a deterioration of both physical and psychological features. There was an increase in central hyperexcitability (cold hyperalgesia, reduced NFR threshold, reduced elbow extension ROM during the BPPT) and reduced neck motion, in conjunction with increased psychological distress and pain catastrophization. These measures returned to levels demonstrated prior to receiving cervical RFN. There was a trend for local and distal PPT measures to deteriorate following the return of pain (although not reaching significance), such that they were not significantly different to original measures at commencement of the study. There was no change in EMG measures during performance of the CCFT, supporting other literature indicating that impaired neuromuscular control is not solely related to pain [64]. Worsening psychological distress and pain catastrophization on return of pain again demonstrated their interaction with pain. This contrasted with posttraumatic stress measures. Posttraumatic stress measures did not improve following reduction of pain, or worsen significantly following the return of pain, suggesting that chronic posttraumatic stress symptoms in the individuals in this study with chronic WAD were independent of pain. 8.6 Low Disability or Low Pain Catatastrophization Predicts Success of Cervical RFN Individuals undergoing cervical RFN demonstrated significant improvements in physical and psychological manifestations of chronic WAD. However, not all individuals improved, which is consistent with the literature, which reports that approximately 70% of individuals have successful reduction of pain post-cervical RFN [61,328]. Information is sparse regarding features which may determine success of cervical RFN. The only variable documented is midline tenderness [303]. Some of the physical and psychological features evident in chronic WAD are associated with poor prognosis [6,35,230,231] and it was questioned whether these features predicted outcomes following cervical RFN. Of the

166 individuals undergoing cervical RFN, 13 reported a less than successful outcome (Global Rating of Change (GROC) < 4). To determine which variables independently predicted success of cervical RFN, various measures (pain, disability, widespread sensory hypersensitivity (combination cold and pressure hyperalgesia), local tenderness (cervical pressure pain thresholds), pain catastrophizing and posttraumatic stress severity) were entered into logistic regression models. One model including the variable low pain catastrophization and another model with the variable low disability (Neck Disability Index) independently predicted success of cervical RFN. However, the low specificity of these measures indicated that individuals with high pain catastrophization and high disability were still likely to benefit from cervical RFN. The presence of local hyperalgesia, widespread sensory hypersensitivity or elevated posttraumatic stress symptoms symptoms did not preclude these individuals from reporting success following cervical RFN. It still appears that the best determination of success post-cervical RFN is the initial response to the diagnostic cervical facet joint blocks [345]. 8.7 Overall Significance of Findings The body of research in this thesis demonstrated for the first time that cervical RFN resulted in successful reduction of disability, reductions in central hyperexcitability, pain catastrophization and improvement in neck ROM. The results also supported prior studies demonstrating a significant reduction of pain and psychological distress. Notably, those measures returned to values comparable to a healthy cohort. The changes were not only statistically significant, but effect sizes were large, indicating the clinical relevance of successful treatment with cervical RFN. Thus successful treatment of peripheral nociception with cervical RFN can provide improvements in clinical manifestations that have been previously resistant to conservative care [186]. Another unique finding was that treatment (RFN) directed at peripheral mechanisms (cervical facet joints) reduced clinical features associated with central hyperexcitability and psychological manifestations. This indicates that the peripheral mechanisms were driving the central mechanisms. This has important clinical ramifications and provides the basis for administering treatment of peripheral nociception for individuals with persistent central mechanisms to improve clinical outcomes. Of note, the clinical features demonstrated by individuals in this study undergoing cervical RFN did not

167 predict an adverse outcome to treatment. For individuals fulfilling the appropriate diagnostic criteria, low pain catastrophization and low levels of disability as measured with the NDI predicted a successful response to cervical RFN. 8.8 Implications of Research Effective management of chronic WAD poses significant challenges, as up to 50% of whiplash-injured individuals continue to report symptoms 12 months following the trauma [3]. In fact, 20 to 30% of individuals continue to report moderate to severe pain and disability two to three years post-injury [51,69]. The outcomes of this research help to further explain the relationship between cervical facet joint nociception and persistent symptoms. It has been demonstrated previously that cervical RFN is successful in reducing pain and psychological distress in individuals with chronic WAD [61,225]. Until now, changes in other clinical manifestations had not been demonstrated in individuals undergoing cervical RFN. The reasons for the persistence of many of these clinical features have been speculative, including ineffective treatment [186,434], presence of central hyperexcitability [35,154], presence of posttraumatic stress symptoms [230], hypothalamic-pituitary-adrenal gland (HPA) axis dysfunction [435], and even perceived injustice [264]. Thus, the body of studies within this thesis investigated one aspect of a very complex picture. However, it is clear, that effective treatment of nociception is responsible for not only a reduction in neck pain, but also for improvement in other impairments underlying mechanisms contributing to persistence of symptoms in chronic WAD. Thus, clinically, in individuals with features of chronic WAD that have not responded to conservative care, consideration for cervical RFN would seem appropriate; whilst for those presenting with symptoms suggestive of PTSD, other treatment options would seem to be indicated. Given that conservative treatment has not reduced transition to chronicity for the WAD population [273] or reduced pain and disability in those with chronic WAD [319]; cervical RFN may be an option to assist with reduction of the global burden of WAD. 8.9 Limitations of Research There are limitations to this research that warrant discussion. The predominant limitation in a longitudinal cohort study is the lack of employment of an appropriate placebo

168 control, especially when not controlled by randomization. As such, it is possible that the results observed following RFN resulted for reasons other than being due to the effects of the intervention performed. This is countered by the previous non-response to various conservative therapies, lack of long-term response to the double cervical facet diagnostic blockade procedure, and response to RFN that matched other clinical cohorts studied, thus providing some certainty that the results obtained were due to the intervention studied. Although the studies were powered appropriately to demonstrate the primary aims of the thesis, further participants would have allowed further investigation of different relationships. For example, the non-significant findings in changes in PDS may be as a result of low power of the study. Similarly, increased study participants would have allowed for other predictor variables to be considered for inclusion in the models constructed to investigate which features predicted the success of RFN. During the conduct of this thesis, other research has been completed that may have shaped the measures used in this study if it was undertaken today. In particular, research regarding conditioned pain modulation [149], would have been of assistance in determination of the role of excitation versus inhibition following reduction of nociception that resulted from cervical RFN. Furthermore, brain studies have emerged, which have investigated the underlying mechanisms apparent with individuals with chronic musculoskeletal pain [385,436]. These measures could possibly render some of the measures used in the studies within this body of research obsolete. Finally, the data collection was performed entirely by the author in a clinical environment. As such, the author was not blinded during collection of measures or analyses, and this has the potential to introduce bias. To counteract this potential bias, study aims were not conveyed to participants. However acknowledgement of this limitation is necessary, with hope that in the future, study budgets would allow an independent assessor to collect data Future Research Completion of any scientific endeavor prompts further questions. One of the challenges of prospective cohort studies is the lack of ability to explain how or why specific treatments work [437]. For example, in the series of studies in this thesis, it was observed that physical features, and in particular central hyperexcitability; in conjunction with

169 psychological manifestations improved following reduction of pain with successful cervical RFN, and then deteriorated upon the return of pain. It seems likely that successful reduction of nociception improved pain and central hyperexcitability. However the possibility remains that reduction of psychological distress with pain relief may have been responsible for the change in hyperexcitability. Similarly, disentangling the role of peripheral nociception and impairments underlying central mechanisms is challenging. The results of these studies implicate the role of peripheral mechanisms in central mechanisms, as evidenced by improvements in NFR thresholds, BPPT, PPT and thermal pain thresholds. However, not all of these measures deteriorated (PPT and heat pain thresholds) upon the return of pain, indicating that there are likely different underlying mechanisms apparent for the return of pain for these respective measures. Thus, the clinical measures utilized in this study and others remain as proxies for underlying impairments of mechanisms that have yet to be fully elucidated. Future research will likely require the use of brain imaging studies. Seminowicz and colleagues investigated individuals with chronic low back pain (LBP) [385]. They investigated changes in cortical thickness through the use of structural magnetic resonance imaging (fmri). In their study, individuals underwent surgery or facet joint interventions in an attempt to reduce pain and disability. They found that those individuals who improved as a result of these treatments demonstrated a reversible change in cortical thickness in the varying brain regions associated with pain experience (left dorsolateral prefrontal cortex, primary motor cortex and left anterior insula), together with improved cognitive performance. Thus, improvement in pain and disability was associated with both functional and structural brain changes, with increases in cortical thickness associated with clinical outcomes. This may explain the changes observed in the body of work contained within this thesis. Similarly, in chronic post-traumatic headaches following whiplash injury, individuals who improved in the subsequent 12 months following their injuries, demonstrated reversible changes in voxel-based morphometry in grey matter in various brain regions (anterior cingulate and dorsolateral prefrontal cortex) involved in an individual s pain experience [436]. These changes did not reverse in individuals who did not improve, although an increase in grey matter in antinociceptive brainstem centres, thalamus and cerebellum developed in all individuals developing chronic headaches revealing a biological plausibility

170 for persistent symptoms [436]. Again, the changes in central mechanisms demonstrated here may explain the changes observed in our studies, whereby improvements in central mechanisms were demonstrated. Thus, it would seem important in future research to determine if individuals undergoing diagnostic cervical facet joint injections and cervical RFN demonstrate similar findings. Apkarian and colleagues have produced a series of studies demonstrating that different chronic pain conditions exhibit unique anatomical brain signatures when investigated with fmri [438]. As an example, an individual with chronic LBP will demonstrate different findings on fmri than an individual with chronic pelvic pain or knee osteoarthritis. The author is not aware of any studies that have reported changes in fmri following whiplash injury (apart from Obermann et. al s [436] posttraumatic headache findings as reported above). Apkarian s laboratory also produced a prospective study investigating individuals with LBP. They determined that transition into chronicity corresponded to a functional connection between the medial prefrontal cortex and the nucleus accumbens, suggesting that this pre-existing brain structural connection predisposed individuals to chronic LBP [439]. This has subsequently been confirmed in a validation study [440]. No interventions were applied in Apkarian s trial. Given Apkarian s results, it would seem that a unique brain signature for chronic neck pain following whiplash injury may be possible. Research in this field is warranted as it holds promise for directing future treatment. If individuals with this brain signature underwent successful cervical RFN, then further fmris could determine if this brain signature could be improved, when compared to that of a healthy individual. Obviously, it would be of interest to determine if any residual brain signature remained. Subsequent research could then study the brain signatures of individuals with presence of neck pain post-whiplash injury with other co-morbid conditions, such as PTSD [441]. The remaining brain signature post-cervical RFN in these individuals may lead to a residual brain signature that could lead to a further understanding of underlying mechanisms present in the co-morbid conditions and thereby assist with appropriately targeting these mechanisms (and hence conditions) with other interventions [442]. In the example of PTSD, the influence of cognitive behavioural therapy could be evaluated. Combination treatment of cervical RFN and PTSD could also be evaluated with such assessment methods

171 Recently, repetitive transcranial magnetic stimulation (rtms) has demonstrated promise in treating impairments of underlying central mechanisms [443]. Repetitive TMS has been successful in reducing depression symptoms in individuals who have failed pharmacological management [444]. As chronic pain and co-morbid depression share similar overlapping findings in central mechanisms, rtms shows promise as a future treatment for individuals with chronic WAD. Again, if it was possible to determine an appropriate brain signature of underlying impaired central mechanisms, appropriate treatment with rtms could be delivered to brain regions associated with impaired mechanisms that did not resolve with conservative therapy or cervical RFN. A variation of rtms, transcranial direct current stimulation has been trialled in chronic low back pain, albeit without success [445]. There are other questions of a mechanistic nature that remain which could possibly affect treatment options in the future. Following cervical RFN, there was a reduction in central hyperexcitability but this improvement deteriorated following the return of pain. However, PPT measures did not alter significantly on return of pain. Thus, future research is required to determine if cervical RFN reduces hyperexcitability at the dorsal horn (as indicated by the changes in NFR threshold measures) by reducing inflammation locally within the facet capsule (i.e. reduce peripheral sensitization); or whether these are changes related to change in central inhibitory processes, as suggested by the lack of change in PPT measures upon the return of pain. Measurement of conditioned pain modulation may assist in this regard [149]. Within the basic science realm, many of these mechanisms have been observed in a whiplash model. Local facet capsular inflammation and spinal cord inflammation have been demonstrated [446,447], together with increased glutamatergic response in the dorsal horn [381,384] following a cervical facet joint distraction model. Teasing out these mechanisms remains a challenge, but also holds great promise moving forwards. Researchers in other recalcitrant pain conditions advocate a treatment-based system directed at impairments of the underlying mechanisms [36,448]. If it could be possible to elucidate the mechanisms underlying the presentation of these clinical manifestations in whiplash associated disorders, treatments could hopefully be directed at such. Individuals who reported that cervical RFN was successful continued to report the presence of some ongoing pain and disability. It could be questioned whether further improvement could be gained with successful treatment of features that did not improve

172 Levels of posttraumatic stress symptoms, as measured by the PDS, did not vary either postcervical RFN or upon the return of pain. The number of symptoms, severity of symptoms or individuals obtaining a diagnosis of posttraumatic stress disorder (PTSD) did not significantly change through the series of studies. The sensitivity or specificity of the PDS to predict a diagnosis of posttraumatic stress disorder is unknown. Thus it is possible that the study was under-powered to demonstrate significant improvements in posttraumatic stress measures. Nevertheless, posttraumatic stress symptoms were not affected by pain, as were the other psychological measures (psychological distress and pain catastrophizing). Future research is indicated to determine if concurrent treatment of posttraumatic stress symptoms and cervical RFN might result in greater improvements in neck pain than either treatment alone Other Research Considerations One of the challenges with cervical RFN is the finite effectiveness it provides. Although effective, individuals consistently report improvement over a 7-14 month period [283]. As such, it would be advantageous to find ways to provide long-lasting relief. One trial investigated pragmatic multi-professional management, including pharmacological treatment [273]. Unfortunately, no reduction in transition to chronicity was measured for individuals receiving this multi-professional management. However, no individuals reportedly received cervical RFN as part of the multi-professional management. It would be of benefit to investigate whether multi-professional management including cervical RFN may hold promise in reducing these clinical manifestations and assist with improved treatment outcomes and reduction of chronicity if introduced earlier to individuals post-whiplash injury. It was approximately three to four years following the initial injury when individuals underwent cervical RFN in this research. Thus, by this time, complex physical and psychological clinical manifestations had developed. If nociception was able to be modulated earlier with effective cervical RFN and associated pain reduced, development of some of the clinical features associated with poor prognosis (e.g. cold hyperalgesia) might be prevented. The research would be challenging. Individuals presenting with indictors of a very poor prognosis [231], with likely facet joint involvement [302] would be the target. Of note, prospective studies have demonstrated that these features develop very early (within one month) [35]. Thus ideally, if such a study is medically feasible, cervical RFN would need to

173 be performed within 2-3 weeks post-injury. A more feasible study in the first instance, might be to investigate the responses to the non-destructive MBB, using a long lasting medication; or alternatively, intra-articular regenerative medicine techniques (e.g. platelet rich plasma) that may assist in capsular repair that has been demonstrated in basic science and cadaveric WAD models [20,21]. Other biomarkers in chronic WAD have also been demonstrated. Recently, biomarkers suggestive of ongoing inflammation were demonstrated in blood tests [449]. The presence of these biomarkers was indicative of ongoing moderate to severe symptoms and also correlated with presence of mechanical hyperalgesia [449]. Previous authors demonstrated persistent inflammatory changes in individuals with chronic WAD utilizing PET scans [274]. Similarly, other authors have demonstrated increased interstitial concentrations of interleukin-6 and serotonin in micro-dialysis studies in upper fibres of trapezius that corresponded with the presence of local mechanical hyperalgesia in individuals with chronic whiplash symptoms [170]. Similarly, fibrous fatty infiltrate has been demonstrated in the cervical flexor and extensor musculature [44,168] and is associated with similar clinical manifestations. It is possible that the inflammatory, biochemical and morphometric alterations are resulting from persistent cervical facet joint nociception. Further research could investigate whether successful cervical RFN treatment could change these biomarkers and thus constitute a treatment of such. Stress system dysregulation and HPA axis dysfunction (cortisol production) have also been postulated as reasons for persistence of symptoms in chronic WAD [366,450]. Stress system dysregulation could result from genetic variations in the Catechol O- Methyltransferease (COMT) gene, indicating a possible genetic predisposition to persistent symptoms [451]. Again, investigation of individuals who do and do not respond to cervical RFN (or even diagnostic facet joint injections) should consider this possibility. Of interest, would be whether effective treatment of nociception via RFN could result in improvements in stress system dysregulation, or whether improvements in pain and disability and other clinical manifestations are independent of such measures, which would indicate that treatment directed specifically to these symptoms is warranted in individuals with chronic WAD

174 8.12 Conclusion. Individuals receiving cervical RFN demonstrated improvements in most physical and psychological manifestations of chronic WAD, with deterioration of these measures resulting upon return of pain. These findings indicate that peripheral nociception dynamically modulates these clinical manifestations and needs to be targeted to provide effective management of individuals with chronic WAD with cervical facet joint lesions. The relief gained with cervical RFN is temporary and as shown in this research, physical and psychological measures deteriorate upon return of pain. This research has enhanced understanding of the key role of peripheral nociception in the production of the potentially complex physical and psychological clinical manifestations in whiplash associated disorders. Future research is strongly indicated to determine ways to suppress or eliminate this peripheral nociception through conservative or interventional means or a combination of both

175 References: 1. Evans RW. Whiplash around the world. Headache 1995;35(5): Spitzer WO, Skovron ML, Salmi LR, et al. Scientific monograph of the Quebec Task Force on Whiplash-Associated Disorders: redefining "whiplash" and its management. Spine 1995;20(8 Suppl):1S-73S. 3. Carroll LJ, Holm LW, Hogg-Johnson S, et al. Course and prognostic factors for neck pain in whiplash-associated disorders (WAD): results of the Bone and Joint Decade Task Force on Neck Pain and Its Associated Disorders. Spine 2008;33(4 Suppl):S Kamper SJ, Rebbeck TJ, Maher CG, McAuley JH, Sterling M. Course and prognostic factors of whiplash: A systematic review and meta-analysis. Pain Scholten-Peeters GG, Verhagen AP, Bekkering GE, et al. Prognostic factors of whiplash-associated disorders: a systematic review of prospective cohort studies. Pain 2003;104(1-2): Walton DM, Macdermid JC, Giorgianni AA, Mascarenhas JC, West SC, Zammit CA. Risk factors for persistent problems following acute whiplash injury: update of a systematic review and meta-analysis. J Orthop Sports Phys Ther 2012;43(2): Williams M, Williamson E, Gates S, Lamb S, Cooke M. A systematic literature review of physical prognostic factors for the development of Late Whiplash Syndrome. Spine 2007;32(25):E Williamson E, Williams M, Gates S, Lamb SE. A systematic literature review of psychological factors and the development of late whiplash syndrome. Pain 2008;135(1-2): Suissa S, Harder S, Veilleux M. The relation between initial symptoms and signs and the prognosis of whiplash. Eur Spine J 2001;10(1): Stovner LJ. The nosologic status of the whiplash syndrome: a critical review based on a methodological approach. Spine (Phila Pa 1976) 1996;21(23): Provinciali L, Baroni M. Clinical Approaches to Whiplash Injuries: A Review. Critical Reviews in Physical and Rehabilitation Medicine 1999;11: Tjell C, Tenenbaum A, Rosenhall U. Auditory function in whiplash-associated disorders. Scand Audiol 1999;28(4):

176 13. Treleaven J, Jull G, Sterling M. Dizziness and unsteadiness following whiplash injury: characteristic features and relationship with cervical joint position error. J Rehabil Med 2003;35(1): Ivancic PC, Ito S, Tominaga Y, et al. Whiplash causes increased laxity of cervical capsular ligament. Clin Biomech (Bristol, Avon) 2008;23(2): Kaneoka K, Ono K, Inami S, Hayashi K. Motion analysis of cervical vertebrae during whiplash loading. Spine 1999;24(8): ; discussion Panjabi MM, Cholewicki J, Nibu K, Grauer J, Vahldiek M. Capsular ligament stretches during in vitro whiplash simulations. J Spinal Disord 1998;11(3): Panjabi MM, Pearson AM, Ito S, Ivancic PC, Wang JL. Cervical spine curvature during simulated whiplash. Clin Biomech (Bristol, Avon) 2004;19(1): Pearson A, Ivancic P, Ito S, Panjabi M. Facet joint kinematics and injury mechanism during simulated whiplash. Spine 2004;29(4): Siegmund G, Myers B, Davis M, Bohnet H, Winkelstein B. Mechanical evidence of cervical facet joint capsule injury during whiplash: a cadaveric study using combined shear, compression, and extension loading. Spine 2001;26(19): Stemper B, Yoganandan N, Gennarelli T, Pintar F. Localized cervical facet joint kinematics under physiological and whiplash loading. Journal of Neurosurgery Spine 2005;3: Winkelstein BA, Nightingale RW, Richardson WJ, Myers BS. The cervical facet capsule and its role in whiplash injury: a biomechanical investigation. Spine 2000;25(10): Rauschning W, Jonsson H. Injuries of the Cervical Spine in Automobile Accidents: Pathoanatomic and Clinical Aspects. In: Gunzberg R, Szpalski M, Eds. Whiplash Injuries: Current Concepts in Prevention, Diagnosis, and Treatment of the Cervical Whiplash Syndrome. Philadelphia: Lippincott-Raven, Taylor J, Taylor M. Cervical spine injuries: an autopsy study of 109 blunt injuries. Journal of Musculoskeletal Pain 1996;4(4): Taylor J, Twomey L. Acute injuries to cervical joints: an autopsy study of neck sprain. Spine 1993;18(9):

177 25. Uhrenholt L, Grunnet-Nilsson N, Hartvigsen J. Cervical spine lesions after road traffic accidents: a systematic review. Spine 2002;27(17): ; discussion Barnsley L, Lord SM, Wallis BJ, Bogduk N. The prevalence of chronic cervical zygapophysial joint pain after whiplash. Spine 1995;20(1):20-25; discussion Bogduk N, Aprill C. On the nature of neck pain, discography and cervical zygapophysial joint blocks. Pain 1993;54(2): Lord SM, Barnsley L, Wallis BJ, Bogduk N. Chronic cervical zygapophysial joint pain after whiplash. A placebo-controlled prevalence study. Spine 1996;21(15): ; discussion Kwan O, Friel J. A review and methodologic critique of the literature supporting 'chronic whiplash injury': part I - research articles. Med Sci Monit 2003;9(8):RA Sterling M. A proposed new classification system for whiplash associated disorders-- implications for assessment and management. Man Ther 2004;9(2): Koelbaek Johansen M, Graven-Nielsen T, Schou Olesen A, Arendt-Nielsen L. Generalised muscular hyperalgesia in chronic whiplash syndrome. Pain 1999;83(2): Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Giani C, Zbinden AM, Radanov BP. Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain 2001;17(4): Moog M, Quintner J, Hall T, Zusman M. The late whiplash syndrome: a psychophysical study. Eur J Pain 2002;6(4): Sterling M, Treleaven J, Edwards S, Jull G. Pressure Pain Thresholds in Chronic Whiplash Associated Disorder: Further Evidence of Altered Central Pain Processing. Journal of Musculoskeletal Pain 2002;10(3): Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain 2003;104(3): Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152(3 Suppl):S Bono G, Antonaci F, Ghirmai S, D'Angelo F, Berger M, Nappi G. Whiplash injuries: clinical picture and diagnostic work-up. Clin Exp Rheumatol 2000;18(2 Suppl 19):S

178 38. Dall'Alba PT, Sterling MM, Treleaven JM, Edwards SL, Jull GA. Cervical range of motion discriminates between asymptomatic persons and those with whiplash. Spine 2001;26(19): Jull G. Deep Cervical Flexor Muscle Dysfuntion in Whiplash. Journal of Musculoskeletal Pain 2000;8(1/2): Nederhand MJ, MJ IJ, Hermens HJ, Baten CT, Zilvold G. Cervical muscle dysfunction in the chronic whiplash associated disorder grade II (WAD-II). Spine 2000;25(15): Elert J, Kendall SA, Larsson B, Mansson B, Gerdle B. Chronic pain and difficulty in relaxing postural muscles in patients with fibromyalgia and chronic whiplash associated disorders. J Rheumatol 2001;28(6): Nederhand MJ, Hermens HJ, MJ IJ, Turk DC, Zilvold G. Cervical muscle dysfunction in chronic whiplash-associated disorder grade 2: the relevance of the trauma. Spine 2002;27(10): Elliott J, Jull G, Noteboom JT, Darnell R, Galloway G, Gibbon WW. Fatty infiltration in the cervical extensor muscles in persistent whiplash-associated disorders: a magnetic resonance imaging analysis. Spine 2006;31(22):E Elliott JM, O'Leary S, Sterling M, Hendrikz J, Pedler A, Jull G. Magnetic resonance imaging findings of fatty infiltrate in the cervical flexors in chronic whiplash. Spine (Phila Pa 1976) 2010;35(9): Tjell C, Rosenhall U. Smooth pursuit neck torsion test: a specific test for cervical dizziness. Am J Otol 1998;19(1): Treleaven J, Jull G, Lowchoy N. Standing balance in persistent whiplash: a comparison between subjects with and without dizziness. J Rehabil Med 2005;37(4): Treleaven J, Jull G, LowChoy N. Smooth pursuit neck torsion test in whiplashassociated disorders: relationship to self-reports of neck pain and disability, dizziness and anxiety. J Rehabil Med 2005;37(4): Radanov BP, Begre S, Sturzenegger M, Augustiny KF. Course of psychological variables in whiplash injury--a 2-year follow-up with age, gender and education pair-matched patients. Pain 1996;64(3):

179 49. Peeters GG, Verhagen AP, de Bie RA, Oostendorp RA. The efficacy of conservative treatment in patients with whiplash injury: a systematic review of clinical trials. Spine 2001;26(4):E Carstensen TB. The influence of psychosocial factors on recovery following acute whiplash trauma. Dan Med J 2012;59(12):B Sterling M, Jull G, Kenardy J. Physical and psychological factors maintain long-term predictive capacity post-whiplash injury. Pain 2006;122(1-2): Wenzel HG, Haug TT, Mykletun A, Dahl AA. A population study of anxiety and depression among persons who report whiplash traumas. J Psychosom Res 2002;53(3): Chien A, Eliav E, Sterling M. The development of sensory hypoesthesia after whiplash injury. Clin J Pain 2010;26(8): Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys Med Rehabil Clin N Am 2006;17(2): Staud R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain 2009;145(1-2): Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2012;152(3 Suppl):S Barnsley L, Bogduk N. Medial branch blocks are specific for the diagnosis of cervical zygapophyseal joint pain. Reg Anesth 1993;18(6): Barnsley L. False-positive rates of cervical zygapophysial joint blocks. Clin J Pain 1993;9: Barnsley L, Lord S, Bogduk N. Comparative local anaesthetic blocks in the diagnosis of cervical zygapophysial joint pain. Pain 1993;55(1): Gibson T, Bogduk N, Macpherson J, McIntosh A. Crash characteristics of whiplash associated chronic neck pain. Journal of Musculoskeletal Pain 2000;8: Lord SM, Barnsley L, Wallis BJ, McDonald GJ, Bogduk N. Percutaneous radiofrequency neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J Med 1996;335(23):

180 62. Schneider GM, Smith AD, Hooper A, et al. Minimizing the source of nociception and its concurrent effect on sensory hypersensitivity: an exploratory study in chronic whiplash patients. BMC Musculoskelet Disord 2010;11: Sterling M, Hodkinson E, Pettiford C, Souvlis T, Curatolo M. Psychologic factors are related to some sensory pain thresholds but not nociceptive flexion reflex threshold in chronic whiplash. Clin J Pain 2008;24(2): Sterling M, Jull G, Vicenzino B, Kenardy J, Darnell R. Development of motor system dysfunction following whiplash injury. Pain 2003;103(1-2): Sterling M, Kenardy J. The relationship between sensory and sympathetic nervous system changes and posttraumatic stress reaction following whiplash injury--a prospective study. J Psychosom Res 2006;60(4): Sterling M, Kenardy J. Physical and psychological aspects of whiplash: Important considerations for primary care assessment. Man Ther 2008;13(2): Sterling M, Kenardy J, Jull G, Vicenzino B. The development of psychological changes following whiplash injury. Pain 2003;106(3): Sterling M, Pedler A. A neuropathic pain component is common in acute whiplash and associated with a more complex clinical presentation. Man Ther Radanov B, Sturzenegger M, Di Stefano G. Long-term outcome after whiplash injury: a 2-year follow-up considering features of injury mechanism and somatic, radiologic, and psycholosocial findings. Medicine 1995;74: Ferrari R, Russell AS, Carroll LJ, Cassidy JD. A re-examination of the whiplash associated disorders (WAD) as a systemic illness. Ann Rheum Dis 2005;64(9): Nijs J, Van Oosterwijck J, De Hertogh W. Rehabilitation of chronic whiplash: treatment of cervical dysfunctions or chronic pain syndrome? Clin Rheumatol 2009;28(3): Bener A, Rahman YS, Mitra B. Incidence and severity of head and neck injuries in victims of road traffic crashes: In an economically developed country. Int Emerg Nurs 2009;17(1): Berecki-Gisolf J, Collie A, McClure R. Reduction in health service use for whiplash injury after motor vehicle accidents in : Results from a defined population. J Rehabil Med

181 74. Cassidy JD, Carroll LJ, Cote P, Lemstra M, Berglund A, Nygren A. Effect of eliminating compensation for pain and suffering on the outcome of insurance claims for whiplash injury. N Engl J Med 2000;342(16): Styrke J, Stalnacke BM, Bylund PO, Sojka P, Bjornstig U. A 10-year incidence of acute whiplash injuries after road traffic crashes in a defined population in northern Sweden. Pm R 2012;4(10): Cote P, Hogg-Johnson S, Cassidy JD, Carroll L, Frank JW. The association between neck pain intensity, physical functioning, depressive symptomatology and time-to-claimclosure after whiplash. J Clin Epidemiol 2001;54(3): Radanov BP, Sturzenegger M. The effect of accident mechanism and initial findings on the long-term outcome of whiplash injury. J Musculoskel Pain 1996;4: Khylback M, Thierfelder T, Soderlund A. Prognostic factors in whiplash-associated disorders. International Journal of Rehabilitation Research 2002;25: Hogg-Johnson S, van der Velde G, Carroll LJ, et al. The burden and determinants of neck pain in the general population: results of the Bone and Joint Decade Task Force on Neck Pain and Its Associated Disorders. Spine 2008;33(4 Suppl):S Galasko C, Murray P, Stephenson W. Incidence of whiplash associated disorder. BC Med J 2002;44: Insurance Bureau of British Columbia T. Driving Confidence 2007 annual report. Report. British Columbia: Library and Archives Canada Cataloguing in Publication Data; Blincoe L, Seay A, Zaloshnja E, et al. The Economic Impact of Motor Vehicle Crashes In: Transportation WDDo, ed.: DOT HS Joslin CC, Khan SN, Bannister GC. Long-term disability after neck injury. a comparative study. J Bone Joint Surg Br 2004;86(7): Bogduk N. Whiplash can have lesions. Pain Res Manag 2006;11(3): Bogduk N, Teasell R. Whiplash: the evidence for an organic etiology. Arch Neurol 2000;57(4): Siegmund GP, Winkelstein BA, Ivancic PC, Svensson MY, Vasavada A. The anatomy and biomechanics of acute and chronic whiplash injury. Traffic Inj Prev 2009;10(2):

182 87. Curatolo M, Bogduk N, Ivancic PC, McLean SA, Siegmund GP, Winkelstein BA. The role of tissue damage in whiplash-associated disorders: discussion paper 1. Spine (Phila Pa 1976) 2011;36(25 Suppl):S Farmer CM, Wells JK, Lund AK. Effects of head restraint and seat redesign on neck injury risk in rear-end crashes. Traffic Inj Prev 2003;4(2): Grauer JN, Panjabi MM, Cholewicki J, Nibu K, Dvorak J. Whiplash produces an S- shaped curvature of the neck with hyperextension at lower levels. Spine 1997;22(21): McConnell W, Howard R, Guzman H, et al. Analysis of human test subject kinematic responses to low velocity rear end impacts. 37th Stapp Car Crash Conference; 1993; San Antonio, TX; p Yoganandan N, Kumaresan S, Pintar F. Lower cervical spine finite element analysis, IOS Press, Amsterdam, Cusick J, Pintar F, Yoganandan N. Whiplash syndrome: kinematic factors influencing pain patterns. Spine 2001;26(11): Panjabi MM, Cholewicki J, Nibu K, Grauer JN, Babat LB, Dvorak J. Mechanism of whiplash injury. Clin Biomech (Bristol, Avon) 1998;13(4-5): Bogduk N, Yoganandan N. Biomechanics of the cervical spine Part 3: minor injuries. Clinical Biomechanics 2001;16: Panjabi M, Cholewicki J, Nibu K, al e. Capsular ligament stretches during in vitro whiplash simulations. Journal of Spinal Disorders 1998;11: Panjabi M, Cholewicki J, Nibu K, Grauer J, Babat L, Dvorak J. Mechanism of whiplash injury. Clinical Biomechanics 1998;13: Panjabi M, Ito S, Pearson A, Ivancic P. Injury mechanisms of the cervical intervertebral disc during simulated whiplash. Spine 2004;29(11): Stemper B, Yoganandan N, Pintar F, Rao R. Anterior longitudinal ligament injuries in whiplash may lead to cervical instability. Medical Engineering and Physics 2005;28(6): Maak TG, Ivancic PC, Tominaga Y, Panjabi MM. Side impact causes multiplanar cervical spine injuries. J Trauma 2007;63(6):

183 100. Maak TG, Tominaga Y, Panjabi MM, Ivancic PC. Alar, transverse, and apical ligament strain due to head-turned rear impact. Spine 2006;31(6): Barnsley L, Lord S, Bogduk N. Whiplash Injury. Pain 1994;58: Ivancic PC, Panjabi MM, Tominaga Y, Pearson AM, Elena Gimenez S, Maak TG. Spinal canal narrowing during simulated frontal impact. Eur Spine J 2006;15(6): Hubbard RD, Chen Z, Winkelstein BA. Transient cervical nerve root compression modulates pain: load thresholds for allodynia and sustained changes in spinal neuropeptide expression. J Biomech 2008;41(3): Rothman SM, Kreider RA, Winkelstein BA. Spinal neuropeptide responses in persistent and transient pain following cervical nerve root injury. Spine 2005;30(22): Yoganandan N, Cusick J, Pintar F, Rao R. Whiplash injury determination with conventional spine imaging and cryomicrotomy. Spine 2001;26(22): Eichberger A, Darok M, Steffan H, Leinzinger PE, Bostrom O, Svensson MY. Pressure measurements in the spinal canal of post-mortem human subjects during rear-end impact and correlation of results to the neck injury criterion. Accid Anal Prev 2000;32(2): Panjabi MM, Maak TG, Ivancic PC, Ito S. Dynamic intervertebral foramen narrowing during simulated rear impact. Spine 2006;31(5):E Ide M, Ide J, Yamaga M, Takagi K. Symptoms and signs of irritation of the brachial plexus in whiplash injuries. J Bone Joint Surg Br 2001;83(2): Dilley A, Lynn B, Pang SJ. Pressure and stretch mechanosensitivity of peripheral nerve fibres following local inflammation of the nerve trunk. Pain 2005;117(3): Djouhri L, Wrigley D, Thut PD, Gold MS. Spinal nerve injury increases the percentage of cold-responsive DRG neurons. Neuroreport 2004;15(3): Tominaga Y, Maak TG, Ivancic PC, Panjabi MM, Cunningham BW. Head-turned rear impact causing dynamic cervical intervertebral foramen narrowing: implications for ganglion and nerve root injury. J Neurosurg Spine 2006;4(5): Ivancic PC, Ito S, Tominaga Y, Carlson EJ, Rubin W, Panjabi MM. Effect of rotated head posture on dynamic vertebral artery elongation during simulated rear impact. Clin Biomech (Bristol, Avon) 2006;21(3):

184 113. Vasavada AN, Brault JR, Siegmund GP. Musculotendon and fascicle strains in anterior and posterior neck muscles during whiplash injury. Spine 2007;32(7): Kongsted A, Sorensen JS, Andersen H, Keseler B, Jensen TS, Bendix T. Are early MRI findings correlated with long-lasting symptoms following whiplash injury? A prospective trial with 1-year follow-up. Eur Spine J Yu SW, Sether L, Haughton VM. Facet joint menisci of the cervical spine: correlative MR imaging and cryomicrotomy study. Radiology 1987;164(1): Baumert B, Klaus W, Steffinger D, Schmidt GP, Reiser MF, Baur-Melnyk A. Assessment of the internal craniocervical ligaments with a new magnetic resonance imaging sequence: three-dimensional turbo spin echo with variable flip-angle distribution (SPACE). Magn Reson Imaging Krakenes J, Kaale BR, Moen G, Nordli H, Gilhus NE, Rorvik J. MRI assessment of the alar ligaments in the late stage of whiplash injury--a study of structural abnormalities and observer agreement. Neuroradiology 2002;44(7): Krakenes J, Kaale BR, Moen G, Nordli H, Gilhus NE, Rorvik J. MRI of the tectorial and posterior atlanto-occipital membranes in the late stage of whiplash injury. Neuroradiology 2003;45(9): Krakenes J, Kaale BR, Nordli H, Moen G, Rorvik J, Gilhus NE. MR analysis of the transverse ligament in the late stage of whiplash injury. Acta Radiol 2003;44(6): Krakenes J, Kaale BR, Rorvik J, Gilhus NE. MRI assessment of normal ligamentous structures in the craniovertebral junction. Neuroradiology 2001;43(12): Myran R, Kvistad KA, Nygaard OP, Andresen H, Folvik M, Zwart JA. Magnetic resonance imaging assessment of the alar ligaments in whiplash injuries: a case-control study. Spine 2008;33(18): Vetti N, Krakenes J, Damsgaard E, Rorvik J, Gilhus NE, Espeland A. Magnetic resonance imaging of the alar and transverse ligaments in acute whiplash-associated disorders 1 and 2: a cross-sectional controlled study. Spine (Phila Pa 1976) 36(6):E Vetti N, Krakenes J, Eide GE, Rorvik J, Gilhus NE, Espeland A. MRI of the alar and transverse ligaments in whiplash-associated disorders (WAD) grades 1-2: high-signal changes by age, gender, event and time since trauma. Neuroradiology 2009;51(4):

185 124. Myran R, Zwart JA, Kvistad KA, et al. Clinical Characteristics, Pain, and Disability in Relation to Alar Ligament MRI Findings. Spine (Phila Pa 1976) 36(13):E862-E Slipman CW, Plastaras C, Patel R, et al. Provocative cervical discography symptom mapping. Spine J 2005;5(4): Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Med 2007;8(4): Tanaka Y, Kokubun S, Sato T, Ozawa H. Cervical roots as origin of pain in the neck or scapular regions. Spine 2006;31(17):E Manchikanti L, Pampati V, Fellows B, Baha AG. The inability of the clinical picture to characterize pain from facet joints. Pain Physician 2000;3(2): Cleland JA, Childs JD, Fritz JM, Whitman JM, Eberhart SL. Development of a clinical prediction rule for guiding treatment of a subgroup of patients with neck pain: use of thoracic spine manipulation, exercise, and patient education. Phys Ther 2007;87(1): Cleland JA, Whitman JM, Fritz JM, Palmer JA. Manual physical therapy, cervical traction, and strengthening exercises in patients with cervical radiculopathy: a case series. J Orthop Sports Phys Ther 2005;35(12): Woolf CJ, Bennett GJ, Doherty M, et al. Towards a mechanism-based classification of pain? Pain 1998;77(3): Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983;306(5944): Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288(5472): Nijs J, Van Houdenhove B, Oostendorp RA. Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice. Man Ther 15(2): Nijs J, Meeus M, Van Oosterwijck J, et al. Treatment of central sensitization in patients with 'unexplained' chronic pain: what options do we have? Expert Opin Pharmacother 12(7): Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Evidence, mechanisms, and clinical implications of central hypersensitivity in chronic pain after whiplash injury. Clin J Pain 2004;20(6):

186 137. Basbaum A, Bushnell C, Devor M. Pain: Basic Mechanisms. In: Castro-Lopes J, Raja S, Schmelz M, Eds. Pain 2008: An Updated Review - Refresher Course Syllabus. Seattle: IASP, 2008: Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410(6827): Curatolo M. Clinical Applications of Basic Mechanisms of Musculoskeletal Pain. In: Castro-Lopes J, Raja S, Schmelz M, Eds. Pain 2008: An Updated Review - Refresher Course Syllabus. Seattle: IASP Press, 2008: Kasch H, Bach FW, Jensen TS. Handicap after acute whiplash injury: a 1-year prospective study of risk factors. Neurology 2001;56(12): Shir Y, Pereira JX, Fitzcharles MA. Whiplash and fibromyalgia: an ever-widening gap. J Rheumatol 2006;33(6): Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 2007;36(6): Fernandez-de-Las-Penas C, Galan-Del-Rio F, Fernandez-Carnero J, Pesquera J, Arendt-Nielsen L, Svensson P. Bilateral Widespread Mechanical Pain Sensitivity in Women With Myofascial Temporomandibular Disorder: Evidence of Impairment in Central Nociceptive Processing. J Pain Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 2009;10(6): Raak R, Wallin M. Thermal thresholds and catastrophizing in individuals with chronic pain after whiplash injury. Biol Res Nurs 2006;8(2): Scott D, Jull G, Sterling M. Widespread sensory hypersensitivity is a feature of chronic whiplash-associated disorder but not chronic idiopathic neck pain. Clin J Pain 2005;21(2): Goldsmith R, Wright C, Bell SF, Rushton A. Cold hyperalgesia as a prognostic factor in whiplash associated disorders: a systematic review. Man Ther 2012;17(5): Kasch H, Qerama E, Bach FW, Jensen TS. Reduced cold pressor pain tolerance in non-recovered whiplash patients: a 1-year prospective study. Eur J Pain 2005;9(5):

187 149. Ng TS, Pedler A, Vicenzino B, Sterling M. Less Efficacious Conditioned Pain Modulation and Sensory Hypersensitivity in Chronic Whiplash-associated Disorders in Singapore. Clin J Pain Lemming D, Graven-Nielsen T, Sorensen J, Arendt-Nielsen L, Gerdle B. Widespread pain hypersensitivity and facilitated temporal summation of deep tissue pain in whiplash associated disorder: an explorative study of women. J Rehabil Med 2012;44(8): Chien A, Eliav E, Sterling M. Whiplash (grade II) and cervical radiculopathy share a similar sensory presentation: an investigation using quantitative sensory testing. Clin J Pain 2008;24(7): Chien A, Eliav E, Sterling M. Hypoaesthesia occurs with sensory hypersensitivity in chronic whiplash - Further evidence of a neuropathic condition. Man Ther Sheather-Reid RB, Cohen ML. Psychophysical evidence for a neuropathic component of chronic neck pain. Pain 1998;75(2-3): Banic B, Petersen-Felix S, Andersen OK, et al. Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. Pain 2004;107(1-2): Sterling M, Treleaven J, Jull G. Responses to a clinical test of mechanical provocation of nerve tissue in whiplash associated disorder. Man Ther 2002;7(2): Luomajoki H, Moseley GL. Tactile acuity and lumbopelvic motor control in patients with back pain and healthy controls. Br J Sports Med 2011;45(5): Wand BM, Di Pietro F, George P, O'Connell NE. Tactile thresholds are preserved yet complex sensory function is impaired over the lumbar spine of chronic non-specific low back pain patients: a preliminary investigation. Physiotherapy 2010;96(4): Willer JC. Comparative study of perceived pain and nociceptive flexion reflex in man. Pain 1977;3(1): Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system. Eur J Appl Physiol Occup Physiol 1994;68(3): Petersen-Felix S, Arendt-Nielsen L, Bak P, Fischer M, Bjerring P, Zbinden AM. The effects of isoflurane on repeated nociceptive stimuli (central temporal summation). Pain 1996;64(2):

188 161. Sterling M. Differential development of sensory hypersensitivity and a measure of spinal cord hyperexcitability following whiplash injury. Pain 2010;150(3): Wallin M, Liedberg G, Borsbo B, Gerdle B. Thermal Detection and Pain Thresholds but not Pressure Pain Thresholds Are Correlated With Psychological Factors in Women With Chronic Whiplash-Associated Pain. Clin J Pain Johnston V, Jimmieson NL, Jull G, Souvlis T. Quantitative sensory measures distinguish office workers with varying levels of neck pain and disability. Pain 2008;137(2): Stone AM, Vicenzino B, Lim EC, Sterling M. Measures of central hyperexcitability in chronic whiplash associated disorder--a systematic review and meta-analysis. Man Ther 2013;18(2): Van Oosterwijck J, Nijs J, Meeus M, Paul L. Evidence for central sensitization in chronic whiplash: a systematic literature review. Eur J Pain 2013;17(3): Lim EC, Sterling M, Stone A, Vicenzino B. Central hyperexcitability as measured with nociceptive flexor reflex threshold in chronic musculoskeletal pain: A systematic review. Pain Elliott JM, O'Leary S, Sterling M, Hendrikz J, Pedler A, Jull G. Magnetic resonance imaging findings of fatty infiltrate in the cervical flexors in chronic whiplash. Spine (Phila Pa 1976) 35(9): Elliott J, Sterling M, Noteboom JT, Darnell R, Galloway G, Jull G. Fatty infiltrate in the cervical extensor muscles is not a feature of chronic, insidious-onset neck pain. Clin Radiol 2008;63(6): Uhlig Y, Weber BR, Grob D, Muntener M. Fiber composition and fiber transformations in neck muscles of patients with dysfunction of the cervical spine. J Orthop Res 1995;13(2): Gerdle B, Lemming D, Kristiansen J, Larsson B, Peolsson M, Rosendal L. Biochemical alterations in the trapezius muscle of patients with chronic whiplash associated disorders (WAD)--a microdialysis study. Eur J Pain 2008;12(1): Kumbhare DA, Balsor B, Parkinson WL, et al. Measurement of cervical flexor endurance following whiplash. Disabil Rehabil 2005;27(14):

189 172. Pearson I, Reichert A, De Serres SJ, Dumas JP, Cote JN. Maximal voluntary isometric neck strength deficits in adults with whiplash-associated disorders and association with pain and fear of movement. J Orthop Sports Phys Ther 2009;39(3): Prushansky T, Gepstein R, Gordon C, Dvir Z. Cervical muscles weakness in chronic whiplash patients. Clin Biomech (Bristol, Avon) 2005;20(8): Descarreaux M, Mayrand N, Raymond J. Neuromuscular control of the head in an isometric force reproduction task: comparison of whiplash subjects and healthy controls. Spine J 2007;7(6): Falla D, Farina D. Neuromuscular adaptation in experimental and clinical neck pain. J Electromyogr Kinesiol 2008;18(2): Falla D, Farina D, Dahl MK, Graven-Nielsen T. Muscle pain induces task-dependent changes in cervical agonist/antagonist activity. J Appl Physiol 2007;102(2): Falla D, Farina D, Graven-Nielsen T. Experimental muscle pain results in reorganization of coordination among trapezius muscle subdivisions during repetitive shoulder flexion. Exp Brain Res 2007;178(3): Svensson P, Wang K, Sessle BJ, Arendt-Nielsen L. Associations between pain and neuromuscular activity in the human jaw and neck muscles. Pain 2004;109(3): Falla D, Jull G, Hodges PW. Feedforward activity of the cervical flexor muscles during voluntary arm movements is delayed in chronic neck pain. Exp Brain Res 2004;157(1): Jull G, Kristjansson E, Dall'Alba P. Impairment in the cervical flexors: a comparison of whiplash and insidious onset neck pain patients. Man Ther 2004;9(2): Falla DL, Jull GA, Hodges PW. Patients with neck pain demonstrate reduced electromyographic activity of the deep cervical flexor muscles during performance of the craniocervical flexion test. Spine 2004;29(19): Jull GA, Falla D, Vicenzino B, Hodges PW. The effect of therapeutic exercise on activation of the deep cervical flexor muscles in people with chronic neck pain. Man Ther Kasch H, Stengaard-Pedersen K, Arendt-Nielsen L, Staehelin Jensen T. Headache, neck pain, and neck mobility after acute whiplash injury: a prospective study. Spine 2001;26(11):

190 184. Sterling M, Jull G, Vicenzino B, Kenardy J. Characterization of acute whiplashassociated disorders. Spine 2004;29(2): Woodhouse A, Vasseljen O. Altered motor control patterns in whiplash and chronic neck pain. BMC Musculoskelet Disord 2008;9: Jull G, Sterling M, Kenardy J, Beller E. Does the presence of sensory hypersensitivity influence outcomes of physical rehabilitation for chronic whiplash?--a preliminary RCT. Pain 2007;129(1-2): Stewart MJ, Maher CG, Refshauge KM, Herbert RD, Bogduk N, Nicholas M. Randomized controlled trial of exercise for chronic whiplash-associated disorders. Pain 2007;128(1-2): Daenen L, Nijs J, Raadsen B, Roussel N, Cras P, Dankaerts W. Cervical motor dysfunction and its predictive value for long-term recovery in patients with acute whiplashassociated disorders: a systematic review. J Rehabil Med 2013;45(2): Tjell C, Tenenbaum A, Sandstrom S. Smooth pursuit neck torsion test A specific test for whiplash associated disorders?. Journal of Whiplash & Related Disorders 2002;1(2): Dehner C, Heym B, Maier D, et al. Postural control deficit in acute QTF grade II whiplash injuries. Gait Posture 2008;28(1): Field S, Treleaven J, Jull G. Standing balance: a comparison between idiopathic and whiplash-induced neck pain. Man Ther 2008;13(3): Gosselin G, Rassoulian H, Brown I. Effects of neck extensor muscles fatigue on balance. Clin Biomech (Bristol, Avon) 2004;19(5): Kogler A, Lindfors J, Odkvist LM, Ledin T. Postural stability using different neck positions in normal subjects and patients with neck trauma. Acta Otolaryngol 2000;120(2): Storaci R, Manelli A, Schiavone N, Mangia L, Prigione G, Sangiorgi S. Whiplash injury and oculomotor dysfunctions: clinical-posturographic correlations. Eur Spine J 2006;15(12): Sjostrom H, Allum JH, Carpenter MG, Adkin AL, Honegger F, Ettlin T. Trunk sway measures of postural stability during clinical balance tests in patients with chronic whiplash injury symptoms. Spine (Phila Pa 1976) 2003;28(15):

191 196. Stokell R, Yu A, Williams K, Treleaven J. Dynamic and functional balance tasks in subjects with persistent whiplash: a pilot trial. Man Ther 2011;16(4): Silva AG, Cruz AL. Standing balance in patients with whiplash-associated neck pain and idiopathic neck pain when compared with asymptomatic participants: A systematic review. Physiother Theory Pract 2013;29(1): Heikkila HV, Wenngren BI. Cervicocephalic kinesthetic sensibility, active range of cervical motion, and oculomotor function in patients with whiplash injury. Arch Phys Med Rehabil 1998;79(9): Revel M, Andre-Deshays C, Minguet M. Cervicocephalic kinesthetic sensibility in patients with cervical pain. Arch Phys Med Rehabil 1991;72(5): Treleaven J, Jull G, LowChoy N. The relationship of cervical joint position error to balance and eye movement disturbances in persistent whiplash. Man Ther 2006;11(2): Kristjansson E, Dall'Alba P, Jull G. A study of five cervicocephalic relocation tests in three different subject groups. Clin Rehabil 2003;17(7): Loudon JK, Ruhl M, Field E. Ability to reproduce head position after whiplash injury. Spine (Phila Pa 1976) 1997;22(8): Grip H, Jull G, Treleaven J. Head eye co-ordination using simultaneous measurement of eye in head and head in space movements: potential for use in subjects with a whiplash injury. J Clin Monit Comput 2009;23(1): Montfoort I, Kelders WP, van der Geest JN, et al. Interaction between ocular stabilization reflexes in patients with whiplash injury. Invest Ophthalmol Vis Sci 2006;47(7): Wenngren BI, Pettersson K, Lowenhielm G, Hildingsson C. Eye motility and auditory brainstem response dysfunction after whiplash injury. Acta Otolaryngol 2002;122(3): Treleaven J, Jull G, Grip H. Head eye co-ordination and gaze stability in subjects with persistent whiplash associated disorders. Man Ther 2011;16(3): Kristjansson E, Treleaven J. Sensorimotor function and dizziness in neck pain: implications for assessment and management. J Orthop Sports Phys Ther 2009;39(5): Schubert MC, Minor LB. Vestibulo-ocular physiology underlying vestibular hypofunction. Phys Ther 2004;84(4):

192 209. Ferrari R, Russell AS. The whiplash syndrome--common sense revisited. J Rheumatol 1997;24(4): Gimse R, Tjell C, Bjorgen IA, Saunte C. Disturbed eye movements after whiplash due to injuries to the posture control system. J Clin Exp Neuropsychol 1996;18(2): Heikkila H, Astrom PG. Cervicocephalic kinesthetic sensibility in patients with whiplash injury. Scand J Rehabil Med 1996;28(3): Hildingsson C, Wenngren BI, Bring G, Toolanen G. Oculomotor problems after cervical spine injury. Acta Orthop Scand 1989;60(5): Mallinson A, Longridge N, Peacock C. Dizziness, Imbalance, and Whiplash. Journal of Musculoskeletal Pain 1996;4: Thunberg J, Hellstrom F, Sjolander P, Bergenheim M, Wenngren B-I, Johansson H. Influences on the fusimotor-muscle spindle system from chemosensitive nerve endings in cervical facet joints in the cat: possible implications for whiplash associated disorders. Pain 2001;91: Falla D. Neuromuscular Control of the Cervical Spine in Neck Pain Disorders. In: Graven-Nielsen T, Arendt-Nielsen L, Mense S, Eds. Fundamentals of Musculoskeletal Pain. Seattle: IASP Press, 2008: Peebles JE, McWilliams LA, MacLennan R. A comparison of symptom checklist 90- revised profiles from patients with chronic pain from whiplash and patients with other musculoskeletal injuries. Spine 2001;26(7): Sturzenegger M, Radanov BP, Di Stefano G. The effect of accident mechanisms and initial findings on the long-term course of whiplash injury. J Neurol 1995;242(7): Nederhand MJ, Ijzerman MJ, Hermens HJ, Turk DC, Zilvold G. Predictive value of fear avoidance in developing chronic neck pain disability: consequences for clinical decision making. Arch Phys Med Rehabil 2004;85(3): Sterling M, Chadwick BJ. Psychologic processes in daily life with chronic whiplash: relations of posttraumatic stress symptoms and fear-of-pain to hourly pain and uptime. Clin J Pain 2010;26(7): Nijs J, Inghelbrecht E, Daenen L, et al. Long-term functioning following whiplash injury: the role of social support and personality traits. Clin Rheumatol 2011;30(7):

193 221. Gargan M, Bannister G, Main C, Hollis S. The behavioural response to whiplash injury. J Bone Joint Surg Br 1997;79(4): Mykletun A, Glozier N, Wenzel HG, et al. Reverse causality in the association between whiplash and symptoms of anxiety and depression: the HUNT study. Spine (Phila Pa 1976) 2011;36(17): Wenzel HG, Vasseljen O, Mykletun A, Nilsen TI. Pre-injury health-related factors in relation to self-reported whiplash: longitudinal data from the HUNT study, Norway. Eur Spine J 2012;21(8): Rebbeck T, Sindhusake D, Cameron I, et al. A prospective cohort study of health outcomes following whiplash associated disorders in an Australian population. Injury Prevention 2006;12: Wallis BJ, Lord SM, Bogduk N. Resolution of psychological distress of whiplash patients following treatment by radiofrequency neurotomy: a randomised, double-blind, placebo-controlled trial. Pain 1997;73(1): Drottning M, Staff P, Levin L, Malt U. Acute emotional response to common whiplash predicts subsequent pain complaints: a prospective study of 107 subjects sustaining whiplash injury. Nord J Psychiatry 1995;49: Kenardy J, Dunne R. Traumatic injury and traumatic stress. Spine (Phila Pa 1976) 2012;36(25 Suppl):S Pedler A, Sterling M. Patients with chronic whiplash can be subgrouped on the basis of symptoms of sensory hypersensitivity and posttraumatic stress. Pain 2013;154(9): Buitenhuis J, de Jong PJ, Jaspers JP, Groothoff JW. Relationship between posttraumatic stress disorder symptoms and the course of whiplash complaints. J Psychosom Res 2006;61(5): Sterling M, Hendrikz J, Kenardy J. Compensation claim lodgement and health outcome developmental trajectories following whiplash injury: A prospective study. Pain Sterling M, Hendrikz J, Kenardy J, et al. Assessment and validation of prognostic models for poor functional recovery 12 months after whiplash injury: a multicentre inception cohort study. Pain 2012;153(8):

194 232. Andersen T, Elklit A, Brink O. PTSD Symptoms Mediate the Effect of Attachment on Pain and Somatisation after Whiplash Injury. Clin Pract Epidemiol Ment Health 2013;17(9): Sterling M, Hendrikz J, Kenardy J. Similar factors predict disability and posttraumatic stress disorder trajectories after whiplash injury. Pain 2011;152(6): Dunne RL, Kenardy J, Sterling M. A randomized controlled trial of cognitivebehavioral therapy for the treatment of PTSD in the context of chronic whiplash. Clin J Pain 2012;28(9): Sullivan MJ, Adams H, Martel MO, Scott W, Wideman T. Catastrophizing and perceived injustice: risk factors for the transition to chronicity after whiplash injury. Spine (Phila Pa 1976) 2011;36(25 Suppl):S Turk DC. Chronic pain and whiplash associated disorders: rehabilitation and secondary prevention. Pain Res Manag 2003;8(1): Jaspers JP. Whiplash and post-traumatic stress disorder. Disabil Rehabil 1998;20(11): Mayou RA, Ehlers A, Bryant B. Posttraumatic stress disorder after motor vehicle accidents: 3-year follow-up of a prospective longitudinal study. Behav Res Ther 2002;40(6): O'Donnell ML, Creamer M, Bryant RA, Schnyder U, Shalev A. Posttraumatic disorders following injury: an empirical and methodological review. Clin Psychol Rev 2003;23(4): Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. J Rehabil Res Dev 2003;40(5): Chibnall JT, Duckro PN. Post-traumatic stress disorder in chronic post-traumatic headache patients. Headache 1994;34(6): Hickling EJ, Blanchard EB, Silverman DJ, Schwarz SP. Motor vehicle accidents, headaches and post-traumatic stress disorder: assessment findings in a consecutive series. Headache 1992;32(3): Taylor S, Fedoroff IC, Koch WJ, Thordarson DS, Fecteau G, Nicki RM. Posttraumatic stress disorder arising after road traffic collisions: patterns of response to cognitive-behavior therapy. J Consult Clin Psychol 2001;69(3):

195 244. Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance? Clin Psychol Rev 2001;21(6): Sullivan M, Bishop S, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess 1995;7: Sullivan MJ, Thorn B, Haythornthwaite JA, et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain 2001;17(1): Buitenhuis J, de Jong PJ, Jaspers JP, Groothoff JW. Catastrophizing and causal beliefs in whiplash. Spine (Phila Pa 1976) 2008;33(22): ; discussion Sullivan MJ, Stanish W, Sullivan ME, Tripp D. Differential predictors of pain and disability in patients with whiplash injuries. Pain Res Manag 2002;7(2): Rivest K, Cote JN, Dumas JP, Sterling M, De Serres SJ. Relationships between pain thresholds, catastrophizing and gender in acute whiplash injury. Man Ther 2010;15(2): Sullivan MJ, Adams H, Rhodenizer T, Stanish WD. A psychosocial risk factor-- targeted intervention for the prevention of chronic pain and disability following whiplash injury. Phys Ther 2006;86(1): Turner JA, Aaron LA. Pain-related catastrophizing: what is it? Clin J Pain 2001;17(1): Wade JB, Riddle DL, Thacker LR. Is pain catastrophizing a stable trait or dynamic state in patients scheduled for knee arthroplasty? Clin J Pain 2012;28(2): Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain 2000;85(3): Buitenhuis J, Jaspers JP, Fidler V. Can kinesiophobia predict the duration of neck symptoms in acute whiplash? Clin J Pain 2006;22(3): Nieto R, Miro J, Huguet A. The fear-avoidance model in whiplash injuries. Eur J Pain 2009;13(5): Turk DC, Robinson JP, Sherman JJ, Burwinkle T, Swanson K. Assessing fear in patients with cervical pain: development and validation of the Pictorial Fear of Activity Scale- Cervical (PFActS-C). Pain 2008;139(1): Pedler A, Sterling M. Assessing Fear-Avoidance Beliefs in Patients With Whiplash- Associated Disorders: A Comparison of 2 Measures. Clin J Pain

196 258. Pedler A, Sterling M. Assessing Fear-Avoidance Beliefs in Patients With Whiplash- Associated Disorders: A Comparison of 2 Measures. Clin J Pain Kamper SJ, Maher CG, Menezes Costa Lda C, McAuley JH, Hush JM, Sterling M. Does fear of movement mediate the relationship between pain intensity and disability in patients following whiplash injury? A prospective longitudinal study. Pain 2012;153(1): Carroll LJ, Cassidy JD, Cote P. The role of pain coping strategies in prognosis after whiplash injury: passive coping predicts slowed recovery. Pain 2006;124(1-2): Buitenhuis J, Spanjer J, Fidler V. Recovery from acute whiplash: the role of coping styles. Spine (Phila Pa 1976) 2003;28(9): Kivioja J, Jensen I, Lindgren U. Early coping strategies do not influence the prognosis after whiplash injuries. Injury 2005;36(8): Carroll LJ, Cassidy JD, Cote P. Frequency, timing, and course of depressive symptomatology after whiplash. Spine (Phila Pa 1976) 2006;31(16):E Sullivan MJ, Thibault P, Simmonds MJ, Milioto M, Cantin AP, Velly AM. Pain, perceived injustice and the persistence of post-traumatic stress symptoms during the course of rehabilitation for whiplash injuries. Pain 2009;145(3): de Jong JR, Vangronsveld K, Peters ML, et al. Reduction of pain-related fear and disability in post-traumatic neck pain: a replicated single-case experimental study of exposure in vivo. J Pain 2008;9(12): Elbers NA, Akkermans AJ, Cuijpers P, Bruinvels DJ. Procedural justice and quality of life in compensation processes. Injury Bostick GP, Ferrari R, Carroll LJ, et al. A population-based survey of beliefs about neck pain from whiplash injury, work-related neck pain, and work-related upper extremity pain. Eur J Pain Holm LW, Carroll LJ, Cassidy JD, Skillgate E, Ahlbom A. Expectations for recovery important in the prognosis of whiplash injuries. PLoS Med 2008;5(5):e Engel GL. The need for a new medical model: a challenge for biomedicine. Science 1977;196(4286): Hoffman BM, Papas RK, Chatkoff DK, Kerns RD. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol 2007;26(1):

197 271. Richardson G, McGrath P. Cognitive-behavioural therapy for migraine headaches: a minimal-therapist-contact approach verus a clinic-based approach. Headache 2005;29: Vlaeyen J, Teeken-Gruben N, Goossens M, et al. Cognitive-educational treatment of fibromyalgia: a randomised clinical trial. 1. Clinical effects. J Rheumatol 1996;23: Jull G, Kenardy J, Hendrikz J, Cohen M, Sterling M. Management of acute whiplash: A randomized controlled trial of multidisciplinary stratified treatments. Pain 2013;154(9): Linnman C, Appel L, Fredrikson M, et al. Elevated [11C]-D-deprenyl uptake in chronic Whiplash Associated Disorder suggests persistent musculoskeletal inflammation. PLoS One 2011;6(4):e Kosek E, Ordeberg G. Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successful treatment. Eur J Pain 2000;4(3): Sterling M, McLean SA, Sullivan MJ, Elliott JM, Buitenhuis J, Kamper SJ. Potential processes involved in the initiation and maintenance of whiplash-associated disorders: discussion paper 3. Spine (Phila Pa 1976) 2012;36(25 Suppl):S Chen C, Lu Y, Cavanaugh J, Kallakuri S, Patwardhan A. Recording of neural activity from goat cervical facet joint capsule using custom-designed miniature electrodes. Spine 2005;30(12): Chen C, Lu Y, Kallakuri S, Patwardhan A, Cavanaugh J. Distribution of A-delta and C-fiber receptors in the cervical facet joint capsule and their response to stretch. Journal of Bone and Joint Surgery 2006;88 - A(8): Kallakuri S, Singh A, Chen C, Cavanaugh JM. Demonstration of substance P, calcitonin gene-related peptide, and protein gene product 9.5 containing nerve fibers in human cervical facet joint capsules. Spine 2004;29(11): Lee K, Franklin A, Davis M, Winkelstein B. Tensile cervical facet capsule ligament mechanics: failure and subfailure responses in the rat. Journal of Biomechanics Lee K, Thinnes J, Gokhin D, Winkelstein B. A novel rodent neck pain model of facetmediated behavioural hypersensitivity: implications for persistent pain and whiplash injury. Journal of Neuroscience Methods 2004;137:

198 282. Lu Y, Chen C, Kallakuri S, Patwardhan A, Cavanaugh J. Neurophysiological and biomechanical characterization of goat cervical facet joint capsules. Journal of Orthopaedic Research 2005;23: McDonald GJ, Lord SM, Bogduk N. Long-term follow-up of patients treated with cervical radiofrequency neurotomy for chronic neck pain. Neurosurgery 1999;45(1):61-67; discussion McLain R. Mechanoreceptors endings in human cervical facet joints. Spine 1994;19(5): Stemper B, Yoganandan N, Pintar F. Effects of abnormal posture on capsular ligament elongations in a computational model subjected to whiplash loading. Journal of Biomechanics 2005;38: Aprill C, Dwyer A, Bogduk N. Cervical zygapophyseal joint pain patterns. II: A clinical evaluation. Spine 1990;15(6): Dwyer A, Aprill C, Bogduk N. Cervical zygapophyseal joint pain patterns. I: A study in normal volunteers. Spine 1990;15(6): Cavanaugh JM. Neurophysiology and Neuroanatomy of Neck Pain. In: Yoganandan N, Pintar F, Eds. Frontiers in Whiplash Trauma: Clinical and Biomechanical. Amsterdam: IOS Press, 2000: Coderre T, Katz J, Vaccarino A, et al. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993;52: Rang H, Bevan S, Dray A. Nociceptive peripheral neurons: cellular properties, 3rd edition, Churchill Livingstone, London, Yoganandan N, Pintar FA, Cusick JF. Biomechanical analyses of whiplash injuries using an experimental model. Accid Anal Prev 2002;34(5): Siegmund GP, Davis MB, Quinn KP, et al. Head-turned postures increase the risk of cervical facet capsule injury during whiplash. Spine 2008;33(15): Kallakuri S, Singh A, Lu Y, Chen C, Patwardhan A, Cavanaugh JM. Tensile stretching of cervical facet joint capsule and related axonal changes. Eur Spine J 2008;17(4):

199 294. Quinn KP, Winkelstein BA. Cervical facet capsular ligament yield defines the threshold for injury and persistent joint-mediated neck pain. J Biomech 2007;40(10): Quinn KP, Winkelstein BA. Detection of Altered Collagen Fiber Alignment in the Cervical Facet Capsule After Whiplash-Like Joint Retraction. Ann Biomed Eng Winkelstein BA, Santos DG. An intact facet capsular ligament modulates behavioral sensitivity and spinal glial activation produced by cervical facet joint tension. Spine 2008;33(8): Lee KE, Winkelstein BA. Joint distraction magnitude is associated with different behavioral outcomes and substance P levels for cervical facet joint loading in the rat. J Pain 2009;10(4): IASP. IASP Taxonomy October 6, 2014 [cited October 20, 2014]; Available from: Quinn KP, Dong L, Golder FJ, Winkelstein BA. Neuronal hyperexcitability in the dorsal horn after painful facet joint injury. Pain 2010;151(2): Jull G, Bogduk N, Marsland A. The accuracy of manual diagnosis for cervical zygapophysial joint pain syndromes. Med J Aust 1988;148(5): King W, Lau P, Lees R, Bogduk N. The validity of manual examination in assessing patients with neck pain. Spine J 2007;7(1): Schneider G, Jull G, Thomas K, et al. Derivation of a Clinical Decision Guide in the Diagnosis of Cervical Facet Joint Pain. Arch Phys Med Rehabil 2014;In Press Cohen SP, Bajwa ZH, Kraemer JJ, et al. Factors predicting success and failure for cervical facet radiofrequency denervation: a multi-center analysis. Reg Anesth Pain Med 2007;32(6): Lord SM, Barnsley L, Bogduk N. The utility of comparative local anesthetic blocks versus placebo-controlled blocks for the diagnosis of cervical zygapophysial joint pain. Clin J Pain 1995;11(3): Boswell MV, Shah RV, Everett CR, et al. Interventional techniques in the management of chronic spinal pain: evidence-based practice guidelines. Pain Physician 2005;8(1):

200 306. Abbott J. Validity of manual examination in assessing patients with neck pain. Spine J 2007;(7): Carragee E, Haldeman S, Hurwitz E. The pyrite standard. The Midas touch in the diagnosis of axial pain syndromes. Spine J 2007;7: Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Bmj 2003;326(7379): Reid MC, Lachs MS, Feinstein AR. Use of methodological standards in diagnostic test research. Getting better but still not good. Jama 1995;274(8): Falco FJ, Erhart S, Wargo BW, et al. Systematic Review of Diagnostic Utility and Therapeutic Effectiveness of Cervical Facet Joint Interventions. Pain Physician 2009;12(2): Sehgal N, Shah RV, McKenzie-Brown AM, Everett CR. Diagnostic utility of facet (zygapophysial) joint injections in chronic spinal pain: a systematic review of evidence. Pain Physician 2005;8(2): Engel A, MacVicar J, Bogduk N. A philosophical foundation for diagnostic blocks, with criteria for their validation. Pain Med 2014;15(6): Bogduk N. Cervical Zygaphophysial Joint Pain. Neurosurgery Quarterly 1998;8(2): Bogduk N. The clinical anatomy of the cervical dorsal rami. Spine 1982;7(4): Moore DC, Bridenbaugh LD, Bridenbaugh PO, Tucker GT. Bupivacaine for peripheral nerve block: A comparison with mepivacaine, lidocaine, and tetracaine. Anesthesiology 1970;32(5): Bogduk N. Diagnostic nerve blocks in chronic pain. Best Pract Res Clin Anaesthesiol 2002;16(4): Manchikanti L, Cash KA, Pampati V, Fellows B. Influence of psychological variables on the diagnosis of facet joint involvement in chronic spinal pain. Pain Physician 2008;11(2): Jull G, Trott P, Potter H, et al. A randomized controlled trial of exercise and manipulative therapy for cervicogenic headache. Spine 2002;27(17): ; discussion

201 319. Michaleff ZA, Maher CG, Lin CW, et al. Comprehensive physiotherapy exercise programme or advice for chronic whiplash (PROMISE): a pragmatic randomised controlled trial. Lancet 2014;pii: S (14) doi: /S (14) Blanchard EB, Hickling EJ, Devineni T, et al. A controlled evaluation of cognitive behavioural therapy for posttraumatic stress in motor vehicle accident survivors. Behav Res Ther 2003;41(1): Provinciali L, Baroni M, Illuminati L, Ceravolo MG. Multimodal treatment to prevent the late whiplash syndrome. Scand J Rehabil Med 1996;28(2): Lamb S, Williams M, Williamson E, et al. Managing Injuries of the Neck Trial (MINT): a randomised controlled trial of treatments for whiplash injuries. Health Technol Assess 2012;16(49): Peat G. Targeting treatment for non-specific musculoskeletal pain. Pain 2008;139(3): Bogduk N. Management of Acute and Chronic Neck Pain, 1 edition, Elsevier, Bogduk N. Why Pay For What Does Not Work? Journal of Musculoskeletal Pain 2000;8(1/2): Sapir DA, Gorup JM. Radiofrequency medial branch neurotomy in litigant and nonlitigant patients with cervical whiplash: a prospective study. Spine 2001;26(12):E McDonald G, Lord S, Bogduk N. Long-term follow-up of patients treated with cervical radiofrequency neurotomy for chronic neck pain. Neurosurgery 1999;45(1): Barnsley L. Percutaneous radiofrequency neurotomy for chronic neck pain: outcomes in a series of consecutive patients. Pain Med 2005;6(4): Carragee EJ, Hurwitz EL, Cheng I, et al. Treatment of neck pain: injections and surgical interventions: results of the Bone and Joint Decade Task Force on Neck Pain and Its Associated Disorders. Spine 2008;33(4 Suppl):S Falco FJ, Manchikanti L, Datta S, et al. Systematic review of the therapeutic effectiveness of cervical facet joint interventions: an update. Pain Physician 2012;15(6):E Sehgal N, Shah RV, McKenzie-Brown AM, Everett CR. Diagnostic utility of facet (zygapophysial) joint injections in chronic spinal pain: a systematic review of evidence. Pain Physician 2007;8(2):

202 332. Lord SM, Bogduk N. Radiofrequency procedures in chronic pain. Best Pract Res Clin Anaesthesiol 2002;16(4): van Wijk RMAW, Geurts JWM, Lousberg R, et al. Psychological Predictors of Substantial Pain Reduction after Minimally Invasive Radiofrequency and Injection Treatments for Chronic Low Back Pain. Pain Medicine 2008;9(2): Van Oosterwijck J, Nijs J, Meeus M, et al. Pain neurophysiology education improves cognitions, pain thresholds, and movement performance in people with chronic whiplash: a pilot study. J Rehabil Res Dev 2011;48(1): Martinez-Segura R, De-la-Llave-Rincon AI, Ortega-Santiago R, Cleland JA, Fernandez-de-Las-Penas C. Immediate changes in widespread pressure pain sensitivity, neck pain, and cervical range of motion after cervical or thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain: a randomized clinical trial. J Orthop Sports Phys Ther 2012;42(9): Sterling M, Pedler A, Chan C, Puglisi M, Vuvan V, Vicenzino B. Cervical lateral glide increases nociceptive flexion reflex threshold but not pressure or thermal pain thresholds in chronic whiplash associated disorders: A pilot randomised controlled trial. Man Ther 2010;15(2): Tobbackx Y, Meeus M, Wauters L, et al. Does acupuncture activate endogenous analgesia in chronic whiplash-associated disorders? A randomized crossover trial. Eur J Pain 2012;17(2): Walton DM, Macdermid JC, Nielson W, Teasell RW, Chiasson M, Brown L. Reliability, standard error, and minimum detectable change of clinical pressure pain threshold testing in people with and without acute neck pain. J Orthop Sports Phys Ther 2011;41(9): Herren-Gerber R, Weiss S, Arendt-Nielsen L, et al. Modulation of central hypersensitivity by nociceptive input in chronic pain after whiplash injury. Pain Med 2004;5(4): Prushansky T, Pevzner E, Gordon C, Dvir Z. Cervical radiofrequency neurotomy in patients with chronic whiplash: a study of multiple outcome measures. J Neurosurg Spine 2006;4(5):

203 341. Dumas JP, Arsenault AB, Boudreau G, et al. Physical impairments in cervicogenic headache: traumatic vs. nontraumatic onset. Cephalalgia 2001;21(9): Speldewinde GC. Outcomes of percutaneous zygapophysial and sacroiliac joint neurotomy in a community setting. Pain Med 2010;12(2): Severeijns R, Vlaeyen JW, van den Hout MA, Weber WE. Pain catastrophizing predicts pain intensity, disability, and psychological distress independent of the level of physical impairment. Clin J Pain 2001;17(2): Sullivan MJ, Stanish W, Waite H, Sullivan M, Tripp DA. Catastrophizing, pain, and disability in patients with soft-tissue injuries. Pain 1998;77(3): Lord S, McDonald G, Bogduk N. Percutaneous Radiofrequency Neurotomy of the Cervical Medial Branches: A Validated Treatment for Cervical Zygapophysial Joint Pain. Neurosurgery Quarterly 1998;8(4): Falco FJ, Datta S, Manchikanti L, et al. An updated review of the diagnostic utility of cervical facet joint injections. Pain Physician 2012;15(6):E Teasell RW, McClure JA, Walton D, et al. A research synthesis of therapeutic interventions for whiplash-associated disorder (WAD): part 5 - surgical and injection-based interventions for chronic WAD. Pain Res Manag 2010;15(5): Wasan AD, Jamison RN, Pham L, Tipirneni N, Nedeljkovic SS, Katz JN. Psychopathology predicts the outcome of medial branch blocks with corticosteroid for chronic axial low back or cervical pain: a prospective cohort study. BMC Musculoskelet Disord 2009;10: Fernandez-de-Las-Penas C, Cleland JA, Ortega-Santiago R, de-la-llave-rincon AI, Martinez-Perez A, Pareja JA. Central sensitization does not identify patients with carpal tunnel syndrome who are likely to achieve short-term success with physical therapy. Exp Brain Res 2010;207(1-2): Bouwense SA, Buscher HC, van Goor H, Wilder-Smith OH. Has central sensitization become independent of nociceptive input in chronic pancreatitis patients who fail thoracoscopic splanchnicectomy? Reg Anesth Pain Med 36(6): Sullivan MJ, Neish N. The effects of disclosure on pain during dental hygiene treatment: the moderating role of catastrophizing. Pain 1999;79(2-3):

204 352. Jacobsen PB, Butler RW. Relation of cognitive coping and catastrophizing to acute pain and analgesic use following breast cancer surgery. J Behav Med 1996;19(1): Vernon H, Mior S. The Neck Disability Index: a study of reliability and validity. J Manipulative Physiol Ther 1991;14(7): Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain 2005;6(3): Goldberg D. Manual of the General Health Questionnaire, NFER-Nelson, Windsor, Foa EB, Riggs DS, Gershuny BS. Arousal, numbing, and intrusion: symptom structure of PTSD following assault. Am J Psychiatry 1995;152(1): Sullivan M. The Pain Catastrophizing Scale User Manual. 2009: Manchikanti L, Singh V. Diagnosis of facet joint pain and prediction of success and failure for cervical facet radiofrequency denervation. Reg Anesth Pain Med 2009;34(1):81-82; author reply Cohen SP, Dragovich A, Hurley RW, Bajwa ZH. Author Reply to Dr. Manchikanti: Diagnosis of Facet Joint Pain and Prediction of Scucess and Failure for Cervical Facet Radiofrequency Denervation. Regional Anesthesia and Pain Medicine 2009;34(1): Portney L, Watkins M. Foundations of Clinical Research Applications and Practice, Prentice Hall International (UK) Ltd, London, Prushansky T, Pevzner E, Gordon C, Dvir Z. Performance of cervical motion in chronic whiplash patients and healthy subjects: the case of atypical patients. Spine 2006;31(1): Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006;123(3): Youdas JW, Garrett TR, Suman VJ, Bogard CL, Hallman HO, Carey JR. Normal range of motion of the cervical spine: an initial goniometric study. Phys Ther 1992;72(11): Kongsted A, Bendix T, Qerama E, et al. Acute stress response and recovery after whiplash injuries. A one-year prospective study. Eur J Pain 2008;12(4):

205 365. Jull G, Amiri M, Bullock-Saxton J, Darnell R, Lander C. Cervical musculoskeletal impairment in frequent intermittent headache. Part 1: Subjects with single headaches. Cephalalgia 2007;27(7): McLean SA. The potential contribution of stress systems to the transition to chronic whiplash-associated disorders. Spine (Phila Pa 1976) 2012;36(25 Suppl):S Rhudy JL, France CR, Bartley EJ, Williams AE, McCabe KM, Russell JL. Does pain catastrophizing moderate the relationship between spinal nociceptive processes and pain sensitivity? J Pain 2009;10(8): McLean SA, Clauw DJ, Abelson JL, Liberzon I. The development of persistent pain and psychological morbidity after motor vehicle collision: integrating the potential role of stress response systems into a biopsychosocial model. Psychosom Med 2005;67(5): Passatore M, Roatta S. Influence of sympathetic nervous system on sensorimotor function: whiplash associated disorders (WAD) as a model. Eur J Appl Physiol 2006;98(5): Bogduk N. International Spinal Injection Society guidelines for the performance of spinal injection procedures. 1. Zygapophysial joint blocks. Clin J Pain 1997;13: Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 2012;64(9): Falla D, Bilenkij G, Jull G. Patients with chronic neck pain demonstrate altered patterns of muscle activation during performance of a functional upper limb task. Spine 2004;29(13): Falla D, Jull G, Rainoldi A, Merletti R. Neck flexor muscle fatigue is side specific in patients with unilateral neck pain. Eur J Pain 2004;8(1): Lee KE, Davis MB, Winkelstein BA. Capsular ligament involvement in the development of mechanical hyperalgesia after facet joint loading: behavioral and inflammatory outcomes in a rodent model of pain. J Neurotrauma 2008;25(11): Chua NH, Vissers KC, Arendt-Nielsen L, Wilder-Smith OH. Do diagnostic blocks have beneficial effects on pain processing? Reg Anesth Pain Med 2011;36(4):

206 376. Smith AD, Jull G, Schneider G, Frizzell B, Hooper RA, Sterling M. A comparison of physical and psychological features of responders and non-responders to cervical facet blocks in chronic whiplash. BMC Musculoskelet Disord 2013;14(1): Macbeth G, Razumiejczyk E, Ledesma R. Cliff's Delta Calculator: A non-parametric effect size program for two groups of observations. Univ Psychol 2011;10(2): Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989;27(3 Suppl):S Cohen J. Statistical Power Analysis for the Behavioural Sciences, 2nd edition, Lawrence Erlbaum Associates, Hillsdale, NJ, Jonsson H, Jr., Bring G, Rauschning W, Sahlstedt B. Hidden cervical spine injuries in traffic accident victims with skull fractures. J Spinal Disord 1991;4(3): Dong L, Odeleye AO, Jordan-Sciutto KL, Winkelstein BA. Painful facet joint injury induces neuronal stress activation in the DRG: implications for cellular mechanisms of pain. Neurosci Lett 2008;443(2): Lee KE, Franklin AN, Davis MB, Winkelstein BA. Tensile cervical facet capsule ligament mechanics: failure and subfailure responses in the rat. J Biomech 2006;39(7): Dong L, Quindlen JC, Lipschutz DE, Winkelstein BA. Whiplash-like facet joint loading initiates glutamatergic responses in the DRG and spinal cord associated with behavioral hypersensitivity. Brain Res 2012;1461: Dong L, Winkelstein BA. Simulated whiplash modulates expression of the glutamatergic system in the spinal cord suggesting spinal plasticity is associated with painful dynamic cervical facet loading. J Neurotrauma 2011;27(1): Seminowicz DA, Wideman TH, Naso L, et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci 2011;31(20): Kilo S, Schmelz M, Koltzenburg M, Handwerker HO. Different patterns of hyperalgesia induced by experimental inflammation in human skin. Brain 1994;117 ( Pt 2): Sterling M, Jull G, Carlsson Y, Crommert L. Are cervical physical outcome measures influenced by the presence of symptomatology? Physiother Res Int 2002;7(3):

207 388. Berglund B, Harju EL, Kosek E, Lindblom U. Quantitative and qualitative perceptual analysis of cold dysesthesia and hyperalgesia in fibromyalgia. Pain 2002;96(1-2): Craig AD, Chen K, Bandy D, Reiman EM. Thermosensory activation of insular cortex. Nat Neurosci 2000;3(2): Quintner JL. A study of upper limb pain and paraesthesiae following neck injury in motor vehicle accidents: assessment of the brachial plexus tension test of Elvey. Br J Rheumatol 1989;28(6): Magerl W, Krumova EK, Baron R, Tolle T, Treede RD, Maier C. Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain 2010;151(3): Nederhand MJ, Hermens HJ, MJ IJ, Turk DC, Zilvold G. Chronic neck pain disability due to an acute whiplash injury. Pain 2003;102(1-2): Bogduk N. International Spinal Injection Society guidelines for the performance of spinal injection procedures. Part 1: Zygapophysial joint blocks. Clin J Pain 1997;13(4): International Spine Intervention Society. Percutaneous radiofrequency cervical medial branch neurotomy. In: Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. San Francisco, CA: International Spine Intervention Society, 2004: Linton SJ. A review of psychological risk factors in back and neck pain. Spine (Phila Pa 1976) 2000;25(9): Main CJ, Wood PL, Hollis S, Spanswick CC, Waddell G. The Distress and Risk Assessment Method. A simple patient classification to identify distress and evaluate the risk of poor outcome. Spine (Phila Pa 1976) 1992;17(1): Jenewein J, Wittmann L, Moergeli H, Creutzig J, Schnyder U. Mutual influence of posttraumatic stress disorder symptoms and chronic pain among injured accident survivors: a longitudinal study. J Trauma Stress 2009;22(6): Walton DM, Pretty J, Macdermid JC, Teasell RW. Risk Factors for Persistent Problems Following Whiplash Injury: Results of a Systematic Review and Meta-analysis. J Orthop Sports Phys Ther 2009;39(5):

208 399. Scott W, Wideman TH, Sullivan MJ. Clinically Meaningful Scores on Pain Catastrophizing Before and After Multidisciplinary Rehabilitation: A Prospective Study of Individuals With Subacute Pain After Whiplash Injury. Clin J Pain Smith AD, Jull G, Schneider G, Frizzell B, Hooper RA, Sterling M. Cervical Radiofrequency Neurotomy Reduces Central Hyperexcitability and Improves Neck Movement in Individuals with Chronic Whiplash. Pain Med 2014;15(1): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, American Psychiatric Association, Washington, D.C., Foa EB. Psychological processes related to recovery from a trauma and an effective treatment for PTSD. Ann N Y Acad Sci 1997;821: Foa EB, Meadows EA. Psychosocial treatments for posttraumatic stress disorder: a critical review. Annu Rev Psychol 1997;48: Sullivan MJ, Stanish WD. Psychologically based occupational rehabilitation: the Pain- Disability Prevention Program. Clin J Pain 2003;19(2): Cohen J. A power primer. Psychol Bull 1992;112(1): Foa EB. Posttraumatic Stress Diagnostic Scale Hand Scoring Directory. Minneapolis: National Computer Systems Inc; MacVicar J, Borowczyk JM, MacVicar AM, Loughnan BM, Bogduk N. Cervical medial branch radiofrequency neurotomy in New Zealand. Pain Med 2012;13(5): Foa EB, Cashman L, Jaycox L, Perry, K. The validation of a self-report measure of posttraumatic stress disorder: the posttraumatic diagnostic scale. Psychol Assess 1997;9: Baerwald CG, Laufenberg M, Specht T, von Wichert P, Burmester GR, Krause A. Impaired sympathetic influence on the immune response in patients with rheumatoid arthritis due to lymphocyte subset-specific modulation of beta 2-adrenergic receptors. Br J Rheumatol 1997;36(12): Buitenhuis J, Spanjer J, Fidler V. Recovery from acute whiplash: the role of coping styles. Spine 2003;28(9): Soderlund A, Lindberg P. Whiplash-associated disorders--predicting disability from a process-oriented perspective of coping. Clin Rehabil 2003;17(1):

209 412. Bogduk N. On cervical zygapophysial joint pain after whiplash. Spine (Phila Pa 1976) 2011;36(25 Suppl):S Smith A, Jull G, Schneider G, Frizzell B, Hooper A, Sterling M. Cervical Radiofrequency Neurotomy Reduces Psychological Distress and Pain Catastrophization, but Not Post-Traumatic Stress in Individuals with Chronic WAD.. Pain Res Manag 2013;18(2):e Smith H, McWhorter J, Challa V. Radiofrequency neurolysis in a clinical model: neuropathological correlation. Journal of Neurosurgery 1981;55: Oono Y, Baad-Hansen L, Wang K, Arendt-Nielsen L, Svensson P. Effect of conditioned pain modulation on trigeminal somatosensory function evaluated by quantitative sensory testing. Pain Skljarevski V, Ramadan NM. The nociceptive flexion reflex in humans -- review article. Pain 2002;96(1-2): Oono Y, Wang K, Svensson P, Arendt-Nielsen L. Conditioned pain modulation evoked by a mechanical craniofacial stimulus is not influenced by noxious stimulation of the temporomandibular joint. J Orofac Pain 2012;26(2): Pedler A, Sterling M. Assessing fear-avoidance beliefs in patients with whiplashassociated disorders: a comparison of 2 measures. Clin J Pain 2011;27(6): Manchikanti L, Boswell MV, Singh V, Pampati V, Damron KS, Beyer CD. Prevalence of facet joint pain in chronic spinal pain of cervical, thoracic, and lumbar regions. BMC Musculoskelet Disord 2004;5: Manchukonda R, Manchikanti KN, Cash KA, Pampati V, Manchikanti L. Facet joint pain in chronic spinal pain: an evaluation of prevalence and false-positive rate of diagnostic blocks. J Spinal Disord Tech 2007;20(7): Ritchie C, Hendrikz J, Kenardy J, Sterling M. Derivation of a clinical prediction rule to identify both chronic moderate/severe disability and full recovery following whiplash injury. Pain Cohen SP, Strassels SA, Kurihara C, et al. Outcome predictors for sacroiliac joint (lateral branch) radiofrequency denervation. Reg Anesth Pain Med 2009;34(3): Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989;10(4):

210 424. Koes BW, Bouter LM, van Mameren H, et al. Randomised clinical trial of manipulative therapy and physiotherapy for persistent back and neck complaints: results of one year follow up. Bmj 1992;304(6827): Koes BW, Bouter LM, van Mameren H, et al. The effectiveness of manual therapy, physiotherapy, and treatment by the general practitioner for nonspecific back and neck complaints. A randomized clinical trial. Spine (Phila Pa 1976) 1992;17(1): Asenlof P, Bring A, Soderlund A. The clinical course over the first year of whiplash associated disorders (WAD): pain-related disability predicts outcome in a mildly affected sample. BMC Musculoskelet Disord 2013;14: Walton DM, Carroll LJ, Kasch H, et al. An Overview of Systematic Reviews on Prognostic Factors in Neck Pain: Results from the International Collaboration on Neck Pain (ICON) Project. Open Orthop J 2013;7: Scott W, Wideman TH, Sullivan MJ. Clinically Meaningful Scores on Pain Catastrophizing Before and After Multidisciplinary Rehabilitation: A Prospective Study of Individuals With Subacute Pain After Whiplash Injury. Clin J Pain 2013: Walton D. A review of the definitions of 'recovery' used in prognostic studies on whiplash using an ICF framework. Disabil Rehabil 2008: Sterling M. Does knowledge of predictors of recovery and nonrecovery assist outcomes after whiplash injury? Spine (Phila Pa 1976) 2011;36(25 Suppl):S Fitz-Ritson D. Phasic exercises for cervical rehabilitation after "whiplash" trauma. J Manipulative Physiol Ther 1995;18(1): Pettersson K, Hildingsson C, Toolanen G, Fagerlund M, Bjornebrink J. MRI and neurology in acute whiplash trauma. No correlation in prospective examination of 39 cases. Acta Orthop Scand 1994;65(5): Vetti N, Krakenes J, Eide GE, Rorvik J, Gilhus NE, Espeland A. Are MRI high-signal changes of alar and transverse ligaments in acute whiplash injury related to outcome? BMC Musculoskelet Disord 2011;11: Verhagen AP, Scholten-Peeters GG, van Wijngaarden S, de Bie RA, Bierma-Zeinstra SM. Conservative treatments for whiplash. Cochrane Database Syst Rev 2007;(2):CD

211 435. Gaab J, Baumann S, Budnoik A, Gmunder H, Hottinger N, Ehlert U. Reduced reactivity and enhanced negative feedback sensitivity of the hypothalamus-pituitary-adrenal axis in chronic whiplash-associated disorder. Pain 2005;119(1-3): Obermann M, Nebel K, Schumann C, et al. Gray matter changes related to chronic posttraumatic headache. Neurology 2009;73(12): Shaw WS, Linton SJ, Pransky G. Reducing sickness absence from work due to low back pain: how well do intervention strategies match modifiable risk factors? J Occup Rehabil 2006;16(4): Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain 2011;152(3 Suppl):S Baliki MN, Petre B, Torbey S, et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci 2012;15(8): Mansour AR, Baliki MN, Huang L, et al. Brain white matter structural properties predict transition to chronic pain. Pain 2013;154(10): Kennis M, Rademaker AR, van Rooij SJ, Kahn RS, Geuze E. Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fmri study. F1000Res 2014;2: Lawrence J, Mackey SC. Role of neuroimaging in analgesic drug development. Drugs R D 2008;9(5): Borckardt JJ, Reeves ST, Beam W, et al. A randomized, controlled investigation of motor cortex transcranial magnetic stimulation (TMS) effects on quantitative sensory measures in healthy adults: evaluation of TMS device parameters. Clin J Pain 2011;27(6): Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology 2009;34(2): O'Connell NE, Cossar J, Marston L, et al. Transcranial direct current stimulation of the motor cortex in the treatment of chronic nonspecific low back pain: a randomized, doubleblind exploratory study. Clin J Pain 2013;29(1):

212 446. Kras JV, Dong L, Winkelstein BA. Increased interleukin-1alpha and prostaglandin e2 expression in the spinal cord at 1 day after painful facet joint injury: evidence of early spinal inflammation. Spine (Phila Pa 1976) 2014;39(3): Kras JV, Dong L, Winkelstein BA. The prostaglandin E2 receptor, EP2, is upregulated in the dorsal root ganglion after painful cervical facet joint injury in the rat. Spine (Phila Pa 1976) 2014;38(3): Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 2003;102(1-2): Sterling M, Elliott JM, Cabot PJ. The course of serum inflammatory biomarkers following whiplash injury and their relationship to sensory and muscle measures: a longitudinal cohort study. PLoS One 2013;8(10):e Walton DM, Macdermid JC, Russell E, Koren G, Van Uum S. Hair-Normalized Cortisol Waking Response as a Novel Biomarker of Hypothalamic-Pituitary-Adrenal Axis Activity following Acute Trauma: A Proof-of-Concept Study with Pilot Results. Pain Res Treat 2013;2013: McLean SA, Diatchenko L, Lee YM, et al. Catechol O-methyltransferase haplotype predicts immediate musculoskeletal neck pain and psychological symptoms after motor vehicle collision. J Pain 2011;12(1): Hurtig IM, Raak RI, Kendall SA, Gerdle B, Wahren LK. Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups. Clin J Pain 2001;17(4): Sandrini G, Serrao M, Rossi P, Romaniello A, Cruccu G, Willer JC. The lower limb flexion reflex in humans. Prog Neurobiol 2005;77(6): Rhudy JL, France CR. Defining the nociceptive flexion reflex (NFR) threshold in human participants: a comparison of different scoring criteria. Pain 2007;128(3): French DJ, France CR, France JL, Arnott LF. The influence of acute anxiety on assessment of nociceptive flexion reflex thresholds in healthy young adults. Pain 2005;114(3): Elvey R. Brachial plexus tension test and the pathoanatomical origin of arm pain. In: Glasgow E, Twomey L, Eds. Aspects of Manipulative Therapy. Melbourne: Lincoln Institute of Health Sciences, 1979:

213 457. Balster SM, Jull GA. Upper trapezius muscle activity during the brachial plexus tension test in asymptomatic subjects. Man Ther 1997;2(3): Pearcy M, Hindle R. New method for the non-invasive three-dimensional measurement of human back movement. Clin Biomech (Bristol, Avon) 1989;4: Falla D, Dall'Alba P, Rainoldi A, Merletti R, Jull G. Location of innervation zones of sternocleidomastoid and scalene muscles--a basis for clinical and research electromyography applications. Clin Neurophysiol 2002;113(1): Macdermid JC, Walton DM, Avery S, et al. Measurement properties of the neck disability index: a systematic review. J Orthop Sports Phys Ther 2009;39(5): Chien A, Eliav E, Sterling M. Hypoaesthesia occurs with sensory hypersensitivity in chronic whiplash--further evidence of a neuropathic condition. Man Ther 2009;14(2):

214 Appendix 1: Instrumentation Quantitative Sensory Tests: Pressure Pain Thresholds (PPTs) Pressure pain thresholds (PPTs) were measured using a pressure algometer (Somedic AB, Farsta, Sweden). The probe size was 1 cm 2 and the rate of application was set at 40 kpa/sec. PPTs were measured over the articular pillars of C5/6 bilaterally (which is the most common facet joint involved in neck pain, (not involving headaches) following whiplash trauma); over the median nerve trunks anterior to the elbow bilaterally, and at a bilateral remote site (upper one third of the muscle belly of tibialis anterior) as previously described in investigations of chronic WAD [35]. The participants were requested to push a button when the sensation first became painful. Triplicate recordings were taken at each site and the mean value for each site used in the analysis. Thermal Pain Thresholds Thermal pain thresholds were measured bilaterally over the cervical spine using the TSA II Neurosensory Analyzer (Medoc Advanced Medical Systems; Minneapolis, MN, USA). The thermode was placed over the skin of the mid cervical region and preset to 32 C, with the rate of temperature change being 1 C per second. To identify cold pain thresholds (CPT) and heat pain thresholds (HPT), participants were asked to push a switch when the cold or warm sensation first became painful [452]. Triplicate recordings were taken at each site and the mean value for each site used in the analysis. Nociceptive Flexion Reflex The nociceptive flexion reflex (NFR) is a polysynaptic spinal withdrawal reflex that is elicited following activation of nociceptive A-delta afferents [453]. It was performed via electrical stimulation through bipolar surface Ag/AgCl-electrodes (inter electrode distance approximately 2 cm), which were placed just distal to the left lateral malleolus of the ankle (innervation area of the sural nerve). EMG reflex responses to electrical stimulation were recorded from the middle of the biceps femoris and the (Ag/AgCl-electrodes). The participant lay prone and a wedge was placed under the ankle to obtain 30 degrees knee flexion. The EMG signal was amplified and low-pass filtered 0-500Hz by a Multichannel

215 EMG (Noraxon, Scottsdale AZ). Stimulation and recording was controlled and analyzed with custom software developed specifically for this test. A 25ms, train-of-five, 1ms, square-wave impulse (perceived as a single stimulus), was delivered by a computer-controlled constant current stimulator (Digitimer DS7A, England). The current intensity was increased from 2mA in steps of 2mA until a reflex was elicited. The program delivered the impulses at random time intervals, so that the participants were not aware of when the stimulus was going to be applied. In this way, voluntary muscle contraction due to stimulus anticipation was avoided. A reflex response was defined using the standardized peak (NFR interval peak z score) EMG activity from biceps femoris as recommended [454]. The NFR Interval Peak z score is the NFR interval peak (EMG activity 90 to 150ms post-stimulation interval) baseline mean (60ms before stimulation)/baseline SD. Rhudy and France [455], suggest a NFR interval peak z score of greater that be used to define a reflex response. The 90 to 150ms interval was chosen as it avoids possible contamination by low threshold cutaneous flexion reflex, startle reactions, and voluntary movements [455]. The current intensity required to elicit a reflex response was defined as the NFR threshold. Brachial Plexus Provocation Test (BPPT) The brachial plexus provocation test (BPPT) was performed as described previously and in the following sequence: gentle shoulder girdle depression, glenohumeral abduction and external rotation in the coronal plane, forearm supination, wrist and finger extension, and elbow extension [456]. The range of elbow extension was measured at the participants pain threshold using a standard goniometer aligned along the mid humeral shaft, medial epicondyle, and ulnar styloid [457]. If the participant did not experience pain, the test was continued until end of available range. Motor Measures: Range of Motion Active cervical range of motion (ROM) was measured using electromagnetic motion sensors (Fastrak, Polhemus, USA) [38]. One sensor was placed over the C7 spinous process and the other was attached to the top of a light skull cup, which was fitted to the participant s

216 head and firmly tightened, such that the second sensor sat on the vertex of the head. Three trials were performed in each direction (flexion, extension, left and right rotation) and the means of the three trials were used in analysis. A computer program was developed to convert the Euler angles into degrees of freedom of motion for the motion of the head (vertex) relative to the neck (C7 spinous process). The Fastrak has previously been used in trials of neck pain and whiplash participants [64] and has shown to be accurate within +/- 0.2 degrees [458]. Cranio-cervical Flexion Test (CCFT) Surface EMG (Noraxon Tele Myo 900) was used to measure the activity of superficial neck flexor muscles (sternocleidomastoid - SCM) during the five incremental stages of the CCFT as described by Jull [180]. The test was performed in supine and used a pressure biofeedback device (Stabilizer, Chattanooga, USA) placed sub-occipitally behind the neck to guide performance. It was inflated to a baseline of 20mmHg and participants perform craniocervical flexion to increase the pressure by five progressive increments of 2mmHg (22mmHg- 30mmHg). Each pressure level was maintained for 10s and participants rested for 15s between each stage. Myoelectric signals were collected from the SCM muscles using Ag AgCl electrodes (Noraxon, USA) in a bipolar configuration. Electrodes were positioned along the lower one-third of the muscle bellies of the SCM [459]. Signals were amplified and filtered by a 500Hz low pass filter (Noraxon TeleMyo 900, Scottsdale AZ) and sampled at 2000Hz (National Instruments DAQ PCI-6221). EMG data were analyzed as follows: The maximum root mean squared (RMS) value was identified for each trace using a 1s sliding window, incremented in 100ms steps. RMS values were normalized for each participant, by dividing the 1s maximum RMS from each level of the CCFT by the 1s maximum RMS during a standardized head lift. The baseline EMG data (RMS value) obtained at rest (20mmHg) was subtracted from the measured EMG at each level of this test. The normalized RMS data for the left and right SCMs were averaged for analysis [64,180]. Questionnaires: Baseline measures included a description of symptoms, symptom dominance (unilateral or bilateral) and severity, collision parameters, treatments since the collision,

217 compensation status, list of medications and demographic variables including gender, age, marital status, employment status, education level and duration of neck pain as per a standard clinical examination. A single item visual analogue scale (VAS: 0-100mm) was used to measure the participants pain intensity in the cervical spine with (0) described as No Pain and (100) as Worst Pain Imaginable. Self-reported pain and disability was measured in whiplash participants with the Neck Disability Index (NDI) [353]. The NDI consists of 10 items addressing functional activities such as personal care, lifting, reading, work, driving, sleeping, and recreational activities and also pain intensity, concentration, and headache which are rated from no disability (0) to total disability (5). The overall score (out of 100) is calculated by totalling the responses of each individual item and multiplying by 2. A higher score indicates greater pain and disability. It is the questionnaire most utilized in WAD research [460]. The s-lanss is a validated self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs pain scale [354]. It consists of seven items and includes two self-examination items. A score of 12 or greater indicates pain of a predominantly neuropathic nature. It has been used in previous WAD research [461]. All participants completed the General Health Questionnaire 28 (GHQ-28) [355] as a measure of general psychological distress. The General Health Questionnaire-28 (GHQ-28) is a 28-item measure of emotional distress in medical settings that is divided into 4 subscales: somatic symptoms (items 1 to 7), anxiety/insomnia (items 8 to 14), social dysfunction (items 15 to 21), and severe depression (items 22 to 28). Each item has a 4-point rating scale ranging from (0) to (3). The total scores can be used as a measure of psychological distress, with a higher score (>23/24) indicating greater distress. The GHQ-28 has been used in previous research of WAD [67,221]. The Posttraumatic Diagnostic Scale (PDS) [356] was included to assess the presence of symptoms according to the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision; DSM IV TR) diagnostic criteria for posttraumatic stress disorders (PTSD). For every item, the frequency of the 17 PTSD symptoms within 1 week is assessed on a 4-point Likert scale, ranging from 0 (never) to 3 (daily). The items referred to a 1-month period prior to the study period. A total symptom severity score (ranging from 0 to 51) is

218 derived with larger scores indicating greater symptom severity. The original PDS demonstrated high internal consistency and good stability and appeared to be a valid instrument for the assessment of PTSD in survivors of various traumatic events inclusive of motor vehicle collisions [402,403]. Pain catastrophizing was evaluated using the Pain Catastrophizing Scale (PCS) [245]. This is a 13-item questionnaire that describes various thoughts and feelings that individuals can experience when they are in pain, and requires participants to reflect on past pain experiences and to indicate the degree to which each of the items applied to them. Each item has a 5-point rating scale ranging from (0) not at all to (4) all the time and scores provide a total for the PCS. A total cut-off score of 30 reflects that an individual has clinically relevant pain catastrophization [357]. In both WAD groups, the following measures were completed: VAS, NDI, s-lanss, GHQ-28, PDS and PCS. In the HC group, only the GHQ-28 questionnaire was completed

219 Appendix 2: RFN Procedure Local anesthetic, fluoroscopic guidance and sterile technique were utilized for placing the 21 gauge RF cannulae to the expected location of the medial branches of the dorsal rami at the appropriate sites. A grounding pad was placed on the patient and connected to the RF lesion generator. Once the RF cannulae were in proper position based on the AP, oblique, and lateral fluoroscopic imaging, an RF probe was inserted into each cannula for determination of the tissue impedance and then motor stimulation. When it was determined that there was no motor nerve stimulation and the cannulae were considered in proper position, 2% lidocaine was injected through each cannula. After anesthetizing with lidocaine, RF thermocoagulation lesions were made at each site using an RF probe with a 5 mm active tip, heating to the tissue at the tip of the probe to 80 degrees centigrade for 75 seconds. For the C2 3 joint the third occipital nerve was the target. For joints below C2 3 both medial branches that innervated the joint were targeted. A small amount (2 mg) of Celestone Soluspan was injected at each neurotomy site at the conclusion of the procedure to reduce the chance of a post-procedure neuritis. The patient was given post-procedure written instructions and phone numbers to reach the radiologist if necessary

220 Appendix 3: Ethical Clearance Whiplash Associated Disorders: A Prospective Study of the Time Course of Effects of Cervical Medial Branch Neurotomies on Sensory, Motor and Psychological Features of the Disorder was granted ethical approval by the Conjoint Health Ethics Board of the Faculties of Medicine, Nursing and Kinesiology, University of Calgary, and the Affiliated Teaching Institutions. This approval was dated January 8, Ethics ID: E

221 On February 25, 2009, ethics approval was gained from the University of Queensland Medical Research Ethics Committee for Experiments on Humans including Behavioural Research. Project Number:

222 Healthy Controls Consent Form Name of Researcher, Faculty, Department, Telephone & R. Allen Hooper MD, CCFP Faculty of Medicine; Department of Family Medicine T: (x: 3); E: Ashley Smith PT, PhD(student); Michele Sterling PT, PhD; Gwen Jull PT, PhD; Geoff Schneider PT, DSc; Bevan Frizzell MD; R. Allen Hooper MD; Asad Khan PhD Title of Project: Whiplash Associated Disorders: A prospective study of the time course of effects of cervical medial branch Radiofrequency Neurotomies on sensory, motor and psychological features of the disorder. This consent form is only part of the process of informed consent. It should give you the basic idea of what the research is about and what your participation will involve. If you would like more detail about something mentioned here, or information not included here, please ask. Take the time to read this carefully and to understand any accompanying information. You will receive a copy of this form. Background: Longstanding neck pain following a motor vehicle accident affects many people. One significant reason for neck pain that lasts a long time is the presence of injury to the facet joints in your neck. The facet joints in your neck are positioned on the back of the spine and they are surrounded by muscles, ligaments, and a disc. Ongoing neck pain can lead to a change in the way your brain and spinal cord process pain information. This can lead to the sensation of pain in areas of the body that are typically healthy or not injured as a result of a car accident. You may feel pain or discomfort with pressure, thermal or electrical stimulation that you did not feel prior to the car accident. Your ability to accurately use the right neck muscles for postural support and your range of motion may also be affected

223 RadioFrequency Neurotomy (burning of the small pain nerves coming from the facet joints) may help reduce the pain coming from that joint. This may in turn help decrease the amount of pain that you may feel to stimulation in other areas of the body as well. Purpose of the Study: The purpose of this research is to determine if there is a change in sensory responses following RadioFrequency Neurotomy (burning the small pain generating nerves) that blocks the pain coming from the facet joint. We also would like to compare the differences in these sensory responses between those who do and don t respond to Medial Branch Blocks performed in the neck region. These results will also be compared against a group of healthy control subjects. What Would I Have to Do? You will be requested to participate in the following procedures; 1) Medical Information: You will be asked to complete a questionnaire requesting information about yourself, your motor vehicle collision, and your medical history. This information will determine whether you are eligible for the study. You will also be asked to complete another questionnaire concerning your general health status and your current level of distress. This will take approximately minutes to complete. 2) Sensori-Motor Tests: You will be asked to complete two tests involving movement of the neck. One test measures neck range of motion and sensors will be placed on the back of your neck and you will wear a light skull cap to measure this movement. You will be asked to take your head forwards and backwards, to each side and turn your head to each side. The other test will require you to gently nod your head while lying on your back. You will be guided in the test by viewing a dial which tells you how far to nod. Whilst you are nodding your head, electrodes (placed on the skin at the front of your neck) will capture information regarding which muscles are performing this motion and how much they are working. 3) Quantitative Sensory Tests: You will be asked to complete the following tests. Pressure Pain Thresholds: A small pressure sensor will be applied to your neck, arms and legs. As the pressure increases, you will be asked to press a button when you feel it becomes painful. The test will stop at this point. No tissue damage will occur at this low intensity. Any local soreness should ease rapidly

224 Thermal Pain Thresholds. A small thermal sensor is placed on your neck. The temperature is gradually increased or decreased and you will be asked to press a button when you first feel a painful heat or cold, upon which you press a button and the test will stop. No tissue damage will occur as the maximum and minimum temperatures are preset to prevent this. Brachial Plexus Provocation Test. Whilst lying on your back in a relaxed posture, your arm will gently be moved, progressively elongating nerve tissue in your arm. When this becomes painful, the test is completed. Nociceptive Flexion Withdrawal Response. Electrodes will be placed over your Sural Nerve, which is located near your ankle bone on the outside of your leg. The electrodes will send a small electrical current through your nerve, which may be slightly uncomfortable. This electrical stimulation will cause a knee jerk reflex that causes your hamstring muscle at the back of your thigh to contract automatically and quickly bend your knee slightly. Electrodes will also be placed over this muscle to measure its activity. You will not feel anything from these electrodes at the back of your thigh. After the electrical stimulation you will be asked to record the discomfort you felt on a scale. The scale will be anchored with 0=no pain at one end and 10=worst pain imaginable at the other end. If your score on this scale reaches 8 or higher, the test will be ceased. The one session of testing required will be performed at the Advanced Spinal Care Centre. The tests will take minutes to complete. What Type of Personal Information will be Collected? Should you agree to participate, you will be asked to provide your gender and age. A review of your health status and history (including past treatment received) will also be collected to ensure that you are an appropriate candidate for this study. No other personal identifying information will be collected in this study. What are the Risks? There are no significant risks associated with quantitative sensory or sensori-motor testing. You may experience an increase in pain for a very brief period (following QST) as the testing procedure is assessing your pain threshold. The brief increase in pain should only last for a few seconds, but may be mildly noticeable for a few minutes once testing is complete

225 Are there any Reproductive Risks? There are no reproductive risks associated with the testing associated with this research and described above. Will I Benefit if I Take Part? If you agree to participate in this study there may not be a direct medical benefit to you. Your participation in this study may benefit health care professionals focus their treatments more appropriately for their patients with chronic neck pain. Your participation in this study may help researchers develop future studies focused on the treatment of chronic neck pain. Do I Have to Participate? Participation is completely voluntary, anonymous and confidential. Your ability to receive treatment at the Advanced Spinal Care Centre, EFW Radiology or Calgary Health Region is not affected by your participation in this study. This research is not studying the effects of treatment, thus you are free to pursue any aspect of treatment as recommended by your health care team in conjunction with this study. You are free to discontinue participation at any time during the study without jeopardizing your health care. You may notify us personally via telephone or as per the details on this form. The researcher may also withdraw you from the study if your medical condition changes (including sustaining another injury) or if the study is completed sooner than currently anticipated. If new information becomes available that might affect your willingness to participate in this study, you will be informed as soon as possible. What Else Does my Participation Involve? There are no other unique features of this research that have not already been discussed in this research form and will affect you

226 Will I Be Paid For Participating, Or Do I Have To Pay For Anything? There are no costs incurred as a condition of or because of participation in this study. Your parking expenses will be covered. No other financial remuneration is available for participation. Will My Records Be Kept Private? No one except the researcher and his supervisor will be allowed to see any of the answers to the questionnaires. There are no names on the questionnaires. Only group information will be summarized for any presentation or publication of results. The questionnaires are kept in a locked cabinet only accessible by the researcher and his supervisor. The anonymous data will be stored for seven years on a computer disk, at which time, it will be permanently erased. The University of Calgary Conjoint Health Research Ethics Board will have access to the records. If I Suffer A Research-Related Injury, Will I Be Compensated? In the event that you suffer injury as a result of participating in this research, no compensation will be provided to you by EFW Radiology, the Advanced Spinal Care Centre, the University of Calgary, the Calgary Health Region or the Researchers. You still have all your legal rights. Nothing said in this consent form alters your right to seek damages. What Happens if Something goes Wrong? If there was any incident during this testing, testing would be immediately interrupted, and the problem dealt with appropriately by the trained physiotherapist. Your doctor and health-care team would be notified as to this occurrence by written documentation. Signatures (written consent) Your signature on this form indicates that you have understood to your satisfaction the information regarding your participation in the research project and agree to participate as a subject. In no way does this waive your legal rights nor release the investigators, or involved institutions from their legal and professional responsibilities. You are free to withdraw from the study at any time without jeopardizing your health care

227 If you have further questions concerning matters related to this research, please contact: Mr. Ashley Smith (403) (ext: 2) Or Dr. Allen Hooper (403) (ext: 3) If you have any questions concerning your rights as a possible participant in this research, please contact Director, Office of Medical Bioethics, University of Calgary, at This study also adheres to the Guidelines of the ethical review process of The University of Queensland. Whilst you are free to discuss your participation in this study with project staff (contactable on ext. 2), if you would like to speak to an officer of the University not involved in the study, you may contact the Ethics Officer on Participant s Name Signature and Date Investigator/Delegate s Name Signature and Date Witness Name Signature and Date The University of Calgary Conjoint Health Research Ethics Board and University of Queensland Medical Review Ethics Committee (Australia) has approved this research study

228 Group: HC Healthy Control Demographics Subject ID#: Date: General Information: Name: Telephone: H) C) W) Address: Can we send study correspondence by to you? Yes No Date of Birth: / / Age: Male Female Family GP: Occupation: Currently Employed? Highest Level of Education Achieved? Past medical history: Surgeries (dates): Fractures (dates): Serious illness (dates): Motor Vehicle Collision Injuries (dates): Did you require treatment following this MVC? Yes No (Please circle) Sports or other injuries to head, neck, or back: Current Medical history: Current health problems: Current medications taken (inclusive of dose ( size ) and frequency eg. Tylenol 100mg daily:

229 Group: HC Subject ID#: Date: 1) Please indicate what, if any, types of treatment you are presently receiving. a) Manipulation b) Massage c) IMS Acupuncture Trigger Point Injections d) Exercise e) Other (explain) 2) What type of practitioner has been providing the current treatment? a) Physical Therapist b) Chiropractor c) Massage Therapist d) Acupuncturist e) Psychologist f) Other (explain) How often are you attending this treatment (per month)? What is the name of your practitioner? 3) Prior to your current treatment program (if applicable), what other treatments have you had in the past? a) Physical Therapist b) Chiropractor c) Massage Therapist d) Acupuncturist e) Other (explain) Thank you for filling out this form. Please go on to complete the following questionnaires: GHQ

230 Whiplash Group (WAD_R or WAD_NR) Consent Form Name of Researcher, Faculty, Department, Telephone & R. Allen Hooper MD, CCFP Faculty of Medicine; Department of Family Medicine T: (x: 3); E: Ashley Smith PT, PhD(student); Michele Sterling PT, PhD; Gwen Jull PT, PhD; Geoff Schneider PT, DSc; Bevan Frizzell MD; R. Allen Hooper MD; Asad Khan PhD Title of Project: Whiplash Associated Disorders: A prospective study of the time course of effects of cervical medial branch Radiofrequency Neurotomies on sensory, motor and psychological features of the disorder. This consent form is only part of the process of informed consent. It should give you the basic idea of what the research is about and what your participation will involve. If you would like more detail about something mentioned here, or information not included here, please ask. Take the time to read this carefully and to understand any accompanying information. You will receive a copy of this form. Background: Longstanding neck pain following a motor vehicle accident affects many people. One significant reason for neck pain that lasts a long time is the presence of injury to the facet joints in your neck. The facet joints in your neck are positioned on the back of the spine and they are surrounded by muscles, ligaments, and a disc. Ongoing neck pain can lead to a change in the way your brain and spinal cord process pain information. This can lead to the sensation of pain in areas of the body that are typically healthy or not injured as a result of a car accident

231 You may feel pain or discomfort with pressure, thermal or electrical stimulation that you did not feel prior to the car accident. Your ability to accurately use the right neck muscles for postural support and your range of motion may also be affected. RadioFrequency Neurotomy (burning of the small pain nerves coming from the facet joints) may help reduce the pain coming from that joint. This may in turn help decrease the amount of pain that you may feel to stimulation in other areas of the body as well. Purpose of the Study: The purpose of this research is to determine if there is a change in sensory responses following RadioFrequency Neurotomy (burning the small pain generating nerves) that blocks the pain coming from the facet joint. We also would like to compare the differences in these sensory responses between those who do and don t respond to Medial Branch Blocks performed in the neck region. These results will also be compared against a group of healthy control subjects. What would I Have to Do? You will be requested to participate in the following procedures; 1) Medical Information: You will be asked to complete a questionnaire requesting information about yourself, your motor vehicle collision, and your medical history. This information will determine whether you are eligible for the study. You will also be asked to complete five questionnaires concerning your pain and your ability to perform functional activities, as well as your current level of distress. This will take approximately minutes to complete. 2) Sensori-Motor Tests: You will be asked to complete two tests involving movement of the neck. One test measures neck range of motion and sensors will be placed on the back of your neck and you will wear a light skull cap to measure this movement. You will be asked to take your head forwards and backwards, to each side and turn your head to each side. The other test will require you to gently nod your head while lying on your back. You will be guided in the test by viewing a dial which tells you how far to nod. Whilst you are nodding your head, electrodes (placed on the skin at the front of your neck) will capture information regarding which muscles are performing this motion and how much they are working

232 3) Quantitative Sensory Tests: You will be asked to complete the following tests. Pressure Pain Thresholds: A small pressure sensor will be applied to your neck, arms and legs. As the pressure increases, you will be asked to press a button when you feel it becomes painful. The test will stop at this point. No tissue damage will occur at this low intensity. Any local soreness should ease rapidly. Thermal Pain Thresholds. A small thermal sensor is placed on your neck. The temperature is gradually increased or decreased and you will be asked to press a button when you first feel a painful heat or cold, upon which you press a button and the test will stop. No tissue damage will occur as the maximum and minimum temperatures are preset to prevent this. Brachial Plexus Provocation Test. Whilst lying on your back in a relaxed posture, your arm will gently be moved, progressively elongating nerve tissue in your arm. When this becomes painful, the test is completed. Nociceptive Flexion Withdrawal Response. Electrodes will be placed over your Sural Nerve, which is located near your ankle bone on the outside of your leg. The electrodes will send a small electrical current through your nerve, which may be slightly uncomfortable. This electrical stimulation will cause a knee jerk reflex that causes your hamstring muscle at the back of your thigh to contract automatically and quickly bend your knee slightly. Electrodes will also be placed over this muscle to measure its activity. You will not feel anything from these electrodes at the back of your thigh. After the electrical stimulation you will be asked to record the discomfort you felt on a scale. The scale will be anchored with 0=no pain at one end and 10=worst pain imaginable at the other end. If your score on this scale reaches 8 or higher, the test will be ceased. The testing will be performed after the Medial Branch Blocks have been performed and again immediately preceding RadioFrequency Neurotomy (approximately 6 months later) if you are progressing to this procedure (WAD-RF group). Further follow-up measures will be performed at the following time periods: 1 month, 3 months and at approximately 7-12 months following RadioFrequency Neurotomy (i.e. when the pain returns to it s original level). We will call you to remind you of your appointments. If you do not proceed to RadioFrequency Neurotomy (WAD-C group), the testing will be completed one month after the Medial Branch Blocks have been completed

233 Thus, you will be eligible for the study if you have Medial Branch Blocks performed to your neck region. All testing will be performed at the Advanced Spinal Care Centre where you had your diagnostic Medial Branch Blocks performed. The testing will take approximately minutes to complete. What Type of Personal Information will be Collected? Should you agree to participate, you will be asked to provide your gender and age. A review of your health status and history (including past treatment received) will also be collected to ensure that you are an appropriate candidate for this study. No other personal identifying information will be collected in this study. What are the Risks? There are no significant risks associated with quantitative sensory or sensori-motor testing. You may experience an increase in pain for a very brief period (following QST) as the testing procedure is assessing your pain threshold. The brief increase in pain should only last for a few seconds, but may be mildly noticeable for a few minutes once testing is complete. You may experience a change in pain thresholds in the regions that are being tested following the RadioFrequency Neurotomy procedure. The decrease in your pain in your neck following the Radiofrequency Neurotomy procedure is most often temporary (between 7-12 months), therefore the change in pain thresholds may only be temporary as well. There is no guarantee that you will experience a change in pain thresholds following the RadioFrequency Neurotomy procedure. Are there any Reproductive Risks? There are no reproductive risks associated with the testing associated with this research and described above. You will not be a candidate for RadioFrequency Neurotomy if you are pregnant

234 Will I Benefit if I Take Part? If you agree to participate in this study there may not be a direct medical benefit to you. Your participation in this study may benefit health care professionals focus their treatments more appropriately for their patients with chronic neck pain. Your participation in this study may help researchers develop future studies focused on the treatment of chronic neck pain. Do I Have to Participate? Participation is completely voluntary, anonymous and confidential. Your ability to receive RadioFrequency Neurotomy is not affected by your participation in this study. This research is not studying the effects of treatment, thus you are free to pursue any aspect of treatment as recommended by your health care team in conjunction with this study. You are free to discontinue participation at any time during the study without jeopardizing your health care. You may notify us personally via telephone or as per the details on this form. The researcher may also withdraw you from the study if your medical condition changes (including sustaining another injury) or if the study is completed sooner than currently anticipated. If new information becomes available that might affect your willingness to participate in this study, you will be informed as soon as possible. What Else Does my Participation Involve? There are no other unique features of this research that have not already been discussed in this research form and will affect you. Will I Be Paid For Participating, Or Do I Have To Pay For Anything? There are no costs incurred as a condition of or because of participation in this study. Your parking expenses will be covered. No other financial remuneration is available for participation

235 Will My Records Be Kept Private? No one except the researcher and his supervisor will be allowed to see any of the answers to the questionnaires. There are no names on the questionnaires. Only group information will be summarized for any presentation or publication of results. The questionnaires are kept in a locked cabinet only accessible by the researcher and his supervisor. The anonymous data will be stored for seven years on a computer disk, at which time, it will be permanently erased. Waiting list subject names within the Advanced Spinal Care Centre will be accessed via usual ancillary clinic staff. The University of Calgary Conjoint Health Research Ethics Board will have access to the records. If I Suffer A Research-Related Injury, Will I Be Compensated? In the event that you suffer injury as a result of participating in this research, no compensation will be provided to you by EFW Radiology, the Advanced Spinal Care Centre, the University of Calgary, the Calgary Health Region or the Researchers. You still have all your legal rights. Nothing said in this consent form alters your right to seek damages. What Happens if Something goes Wrong? If there was any incident during this testing, testing would be immediately interrupted, and the problem dealt with appropriately by the trained physiotherapist. Your doctor and health-care team would be notified as to this occurrence by written documentation. Signatures (written consent) Your signature on this form indicates that you have understood to your satisfaction the information regarding your participation in the research project and agree to participate as a subject. In no way does this waive your legal rights nor release the investigators, or involved institutions from their legal and professional responsibilities. You are free to withdraw from the study at any time without jeopardizing your health care

236 If you have further questions concerning matters related to this research, please contact: Mr. Ashley Smith (403) (ext: 2) Or Dr. Allen Hooper (403) (ext: 3) If you have any questions concerning your rights as a possible participant in this research, please contact Director, Office of Medical Bioethics, University of Calgary, at This study also adheres to the Guidelines of the ethical review process of The University of Queensland. Whilst you are free to discuss your participation in this study with project staff (contactable on ext. 2), if you would like to speak to an officer of the University not involved in the study, you may contact the Ethics Officer on Participant s Name Signature and Date Investigator/Delegate s Name Signature and Date Witness Name Signature and Date The University of Calgary Conjoint Health Research Ethics Board and University of Queensland Medical Review Ethics Committee (Australia) has approved this research study

237 Group: WAD-RF, WAD-C, HC Time Period: Subject ID#: Date: Whiplash Group (WAD_R or WAD_NR) Demographics General Information: Name: Telephone: H) C) W) Address: Can we send study correspondence by to you? Yes No Date of Birth: / / Age: Male Female Family GP: Occupation: Currently Employed? Due to crash? Yes No (Please circle) Highest Level of Education Achieved? Past medical history: Surgeries (dates): Fractures (dates): Serious illness (dates): Sports or other injuries to head, neck, or back: Current Medical history: Current health problems: Current medications taken (inclusive of dose ( size ) and frequency eg. Tylenol 100mg daily:

238 Group: WAD-RF, WAD-C, HC Subject ID#: Time Period: Date: NECK INFORMATION: (Please try to be as specific as possible) 1) Why did you receive injections into the neck region? (Please tick those that apply) a) Neck pain? Right Left b) Headaches? Right Left c) Neck pain & Headaches? d) Shoulder pain? Right Left e) Neck pain & Shoulder pain f) Other PLEASE COMPLETE THE ATTACHED PAIN DRAWING (BODY DIAGRAM) TO INDICATE THE LOCATION OF YOUR PAIN. 2) Approximately, how many weeks have you had the pain in question #1? a) What was the date of your Motor Vehicle Collision Injury? 3) Have you been involved in previous Motor Vehicle Collisions? Yes No Approximate dates (year only) Did you require treatment for these injuries? 4) Is litigation pending as a result of the Motor Vehicle Collision (please circle)? YES NO 5) Please indicate what, if any, types of treatment you are presently receiving. a) Manipulation b) Massage c) IMS Acupuncture Trigger Point Injections d) Exercise e) Other (explain) 6) What type of practitioner has been providing the current treatment? a) Physical Therapist b) Chiropractor c) Massage Therapist d) Acupuncturist e) Psychologist f) Other (explain) How often are you attending this treatment (per month)? What is the name of your practitioner?

239 Group: WAD-RF, WAD-C, HC Subject ID#: Time Period: Date: 7) Prior to your current treatment program (if applicable), what other treatments have you had in the past? a) Physical Therapist b) Chiropractor c) Massage Therapist d) Acupuncturist e) Other (explain) Thank you for filling out this form. Please go on to complete the following questionnaires: NDI, GHQ-28, PDS, PCS & s-lanss Please also complete the Motor Vehicle Collision Description form, so that we can understand more about this collision and it s effect on you

240 Group: WAD-RF, WAD-C, HC Time Period: MOTOR VEHICLE COLLISION DESCRIPTION Subject ID#: Date: Collision Description Check all that apply to you: Single-car crash Two-vehicle crash More than three vehicles Rear-end crash Side crash Rollover Head-on crash Hit guardrail/tree Ran off road You were the Driver Front passenger Rear passenger Describe the vehicle you were in Model year and make: Subcompact car Compact car Mid-sized car Full-sized car Pickup truck Larger than 1 ton vehicle Describe the other vehicle Model year and make: Subcompact car Compact car Mid-sized car Full-sized car Pickup truck Larger than 1 ton vehicle Estimated crash speeds Estimate how fast your vehicle was moving at time of crash. Estimate how fast the other vehicle was moving at time of crash. km km At the time of impact your vehicle was Slowing down Stopped Gaining speed Moving at steady speed At the time of impact the other vehicle was Slowing down Stopped Gaining speed Moving at steady speed During and after the crash, your vehicle Kept going straight, not hitting anything Kept going straight, hitting car in front Was hit by another vehicle Spun around, not hitting anything Spun around, hitting another car Spun around, hitting object other than car Describe yourself during the crash Check only the areas that apply to you: You were unaware of the impending collision. You were aware of the impending crash and relaxed before the collision. You were aware of the impending crash and braced yourself. Your body, torso, and head were facing straight ahead. You had your head, and/or torso turned at the time of collision: Turned to left Turned to right You were intoxicated (alcohol) at the time of crash. You were wearing a seat belt. If yes, does you seat belt have a shoulder harness? Yes No You were holding onto the steering wheel at the time of impact

241 Group: WAD-RF, WAD-C, HC Time Period: Indicate if your body hit something or was hit by any of the following Please draw lines and match the left side to the right side. Head Windshield Face Steering wheel Shoulder Side door Neck Dashboard Chest Car frame Hip Another occupant Knee Seat Foot Seat belt Subject ID#: Date: Check if any of the following vehicle parts broke, bent, or were damaged in your car Windshield Seat frame Knee bolster Steering wheel Side/rear window Other Dash Mirror Other Rear-end collisions only Answer this section only if you were hit from the rear. Does your vehicle have Movable head restraints Fixed, nonmovable head restraints No head restraints Please indicate how your head restraint was positioned at the time of crash.* At the top of the back of your head Midway height of the back of your head Lower height of the back of your head Located at the level of your neck Located at the level of your shoulder blades (upper back) below neck *Estimate the distance between the back of your head and the front of the head restraint. cm All types of collisions Answer this section regardless of the type of crash, indicating those relevant to your case. Yes No Did any of the front or side structures, such as the side door, dashboard, or floorboard of your car, dent inward during the crash? Did the side door touch your body during the crash? Was your hand(s) on the steering wheel or dash during the crash? Did your body slide under the seat belt? Was the door(s) of your vehicle damaged to the point where you could not open the door?

242 Group: WAD-RF, WAD-C, HC Time Period: Subject ID#: Date: Emergency department Yes No Did you go to the emergency department after the accident? What is the name of the emergency department? When did you go (date and time)? Did you go to the emergency department in an ambulance? Did you or another person drive you to the emergency department? Were you hospitalized overnight? Did the emergency department doctor take X-rays? Check what was taken: Skull Neck Low back Arm or leg Did the emergency department doctor give you pain medications? Did the emergency department doctor give you muscle relaxants? Did you have any cuts or lacerations? Did you require any stitching for cuts? Were you given a neck collar or back brace to wear? When did you first notice any pain after injury? Immediately Hours after injury Days after injury If you did not see a doctor for the first time within the first week, indicate why Check all that apply No pain was noticed No appointment schedule available No transportation Work/home schedule conflicts I thought pain would go away I had no insurance or money I self-treated with over-the-counter drugs I took hot showers, used ice, heat Have you been unable to work since injury? Yes No If yes, you were off work partially or completely Please list dates off work: to

243 Group: WAD-RF, WAD-C, HC Time Period: Subject ID#: Date: PATIENT INSTRUCTIONS: It is important for this section to be filled out in detail. CHECK if you have had any single or multiple symptom(s) listed below. Leave row blank if the symptom listed does not apply to you. Symptom List Headache Dizziness Tinnitus (ear ringing) Blurry vision Memory problems Poor concentration Irritability Balance problems Loss of coordination Sensitivity to sound Sensitivity to light Fatigue Anxiety Pain/difficulty swallowing Jaw pain Neck pain/soreness Neck stiffness Shoulder pain/stiffness Arm pain/tingling/numbness Wrist/hand/finger pain/numbness Weakness in arms/legs Upper/mid back pain Chest wall pain (rib) Low back pain/soreness Hip pain Leg pain Leg numbness/tingling Pain shoots down legs Knee pain Ankle/foot pain Other Felt Right After Injury Felt Hours Later Have Symptoms Now Had Similar Symptoms 1-3 Months Before This Injury

244 Group: WAD-RF, WAD-C, HC Subject ID#: Time Period: Date: APPENDIX 4: QUESTIONNAIRES VISUAL ANALOGUE SCALE (VAS) How severe is your pain today (in area that you received diagnostic facet blocks)? Place an x on the line below to indicate how bad you feel your pain is today. No Pain Worst Pain Imaginable Please shade the following pain diagram as per instructions below: Can you please estimate what % of relief of your neck pain that you expect to receive if proceeding to RFN?

245 Group: WAD-RF, WAD-C, HC Time Period: Subject ID#: Date: NECK DISABILITY INDEX This questionnaire has been designed to give the physiotherapist information as to how your neck pain has affected your ability to manage in everyday life. Please answer every section and mark in each section only the ONE box which applies to you. We realize you may consider that two of the statements in any one section relate to you, but please just mark the box which most closely describes your problem over the last 24 hours. SECTION 1 PAIN INTENSITY SECTION 6 CONCENTRATION I have no pain at the moment. The pain is very mild at the moment. The pain is moderate at the moment. The pain is fairly severe at the moment. The pain is very severe at the moment. The pain is the worst imaginable at the moment. SECTION 2 PERSON CARE (Washing, Dressing, etc.) I can look after myself normally without causing extra pain. I can look after myself normally but it causes extra pain. It is painful to look after myself and I am slow and careful. I need some help but manage most of my personal care. I need help every day in most aspects of self care. I do not get dressed, I wash with difficulty and stay in bed. SECTION 3 LIFTING I can lift heavy weights without extra pain. I can lift heavy weights but it gives extra pain. Pain prevents me from lifting heavy weights off the floor, but I can manage if they are conveniently positioned, for example on a table. Pain prevents me from lifting heavy weights, but I can manage light to medium weights if they are conveniently positioned. I can lift very light weights. I cannot lift or carry anything at all. I can concentrate fully when I want to with no difficulty. I can concentrate fully when I want to with slight difficulty. I have a fair degree of difficulty in concentrating when I want to. I have a lot of difficulty in concentrating when I want to. I have a great deal of difficulty in concentrating when I want to. I cannot concentrate at all. SECTION 7 WORK I can do as much work as I want to. I can only do my usual work, but no more. I can do most of my usual work, but no more. I cannot do my usual work. I can hardly do any work at all. I can t do any work at all. SECTION 8 DRIVING I can drive my car without any neck pain. I can drive my car as long as I want with slight pain in my neck. I can drive my car as long as I want with moderate pain in my neck. I can t drive my car as long as I want because of moderate pain in my neck. I can hardly drive at all because of severe pain in my neck. I can t drive my car at all. SECTION 4 READING I can read as much as I want to with no pain in my neck. I can read as much as I want to with slight pain in my neck. I can read as much as I want to with moderate pain in my neck. I can t read as much as I want to because of moderate pain in my neck. I can hardly read at all because of severe pain in my neck. I cannot read at all. SECTION 5 HEADACHES I have no headaches at all. I have slight headaches which come in-frequently. I have moderate headaches which come in-frequently. I have moderate headaches which come frequently. I have severe headaches which come frequently. I have headaches almost all the time. SECTION 9 SLEEPING I have no trouble sleeping. My sleep is slightly disturbed (less than 1 hour sleepless). My sleep is mildly disturbed (1-2 hrs. sleepless). My sleep is moderately disturbed (2-3 hrs. sleepless). My sleep is greatly disturbed (3-5 hrs. sleepless). My sleep is completely disturbed (5-7 hrs. sleepless). SECTION 10 RECREATION I am able to engage in all my recreation activities with no neck pain at all. I am able to engage in all my recreation activities, with some pain in my neck. I am able to engage in most, but not all of my usual recreation activities because of my neck pain. I am able to engage in a few of my usual recreation activities because of pain in my neck. I can hardly do any recreation activities because of pain in my neck. I can t do any recreation activities at all. TOTAL SCORE = /

246 Group: WAD-RF, WAD-C, HC Time Period: 28-Item General Health Questionnaire Subject ID#: Date: We should like to know if you have had any medical complaints, and how your health has been in general, over the past few weeks. Please answer ALL the questions on the following pages simply by underlining the answer which you think most nearly applies to you. Remember that we want to know about present and recent complaints, not those that you had in the past. It is important that you try to answer ALL the questions. Thank you very much for your co-operation. A1. Have you recently been feeling perfectly well and in good health? better than usual same as usual worse than usual much worse than usual A2. Have you recently been feeling in need of some medicine to pick you up? not at all no more than usual rather more than usual much more than usual A3. Have you recently been feeling run down and out of sorts? not at all no more than usual rather more than usual much more than usual A4. Have you recently felt that you are ill? not at all no more than usual rather more than usual much more than usual A5. Have you recently been getting any pains in your head? not at all no more than usual rather more than usual much more than usual A6. Have you recently been getting a feeling of tightness or pressure in your head? not at all no more than usual rather more than usual much more than usual A7. Have you recently been having hot or cold spells? not at all no more than usual rather more than usual much more than usual

247 Group: WAD-RF, WAD-C, HC Time Period: Subject ID#: Date: B1. Have you recently lost much sleep over worry? not at all no more than usual rather more than usual much more than usual B2. Have you recently had difficulty staying asleep once your are off? not at all no more than usual rather more than usual much more than usual B3. Have you recently felt constantly under strain? not at all no more than usual rather more than usual much more than usual B4. Have you recently been getting edgy and bad-tempered? not at all no more than usual rather more than usual much more than usual B5. Have you recently been getting scared or panicky for no good reason? not at all no more than usual rather more than usual much more than usual B6. Have you recently found everything getting on top of you? not at all no more than usual rather more than usual much more than usual B7. Have you recently been feeling nervous and uptight all the time? not at all no more than usual rather more than usual much more than usual

248 Group: WAD-RF, WAD-C, HC Time Period: C1. Have you recently been managing to keep yourself busy and occupied? more so than usual same as usual rather less than usual much less than usual Subject ID#: Date: C2. Have you recently been taking longer over the things you do? quicker than usual same as usual longer than usual much longer than usual C3. Have you recently felt on the whole you were doing things well? better than usual about the same less well than usual much less well C4. Have you recently been satisfied with the way you've carried out your task? more satisfied about the same as usual less satisfied than usual much less satisfied C5. Have you recently felt that you are playing a useful part in things? more so than usual same as usual less useful than usual much less useful C6. Have you recently felt capable of making decisions about things? more so than usual same as usual less so than usual much less capable C7. Have you recently been able to enjoy your normal day-to-day activities? more so than usual same as usual rather less than usual much less than usual

249 Group: WAD-RF, WAD-C, HC Time Period: D1. Have you recently been thinking of yourself as a worthless person? not at all no more than usual rather more than usual much more than usual Subject ID#: Date: D2 Have you recently felt that life is entirely hopeless? not at all no more than usual rather more than usual much more than usual D3. Have you recently felt that life isn't worth living? not at all no more than usual rather more than usual much more than usual D4. Have you recently thought of the possibility that you might do away with yourself? definitely not I don't think so has crossed my mind definitely has D5. Have you recently found at times you couldn't do anything because your nerves were too bad? not at all no more than usual rather more than usual much more than usual D6. Have you recently found yourself wishing you were dead and away from it all? not at all no more than usual rather more than usual much more than usual D7. Have you recently found that the idea of taking your own life kept coming into your mind? definitely not I don't think so has crossed my mind definitely has

250 Group: WAD-RF, WAD-C Time Period: Subject ID#: Date: POST TRAUMATIC DIAGNOSTIC SCALE Part 1 Part 2 Many people have lived through or witnessed a very stressful and traumatic event at some point in their lives. Below is a list of traumatic events. Put a checkmark in the box next to ALL of the events that have happened to you or that you have witnessed. (1) Serious accident, fire, or explosion (for example, an industrial, farm, car, plane or boating accident) (2) Natural disaster (for example, tornado, hurricane, flood, or major earthquake) (3) Non-sexual assault by a family member or someone you know (for example, being mugged, physically attacked, shot, stabbed, or held at gunpoint) (4) Non-sexual assault by a stranger (for example, being mugged, physically attacked, shot, stabbed, or held at gunpoint) (5) Sexual assault by a family member or someone you know (for example, rape or attempted rape) (6) Sexual assault by a stranger (for example, rape or attempted rape) (7) Military combat or a war zone (8) Sexual contact when you were younger than 18 with someone who was 5 or more years older than you (for example, contact with genitals, breasts) (9) Imprisonment (for example, prison inmate, prisoner of war, hostage) (10) Torture (11) Life-threatening illness (12) X Other traumatic event (13) If you marked item 12, specify the traumatic event below. MOTOR VEHICLE COLLISION IF YOU MARKED ANY OF THE ITEMS ABOVE, CONTINUE. IF NOT, STOP HERE. (14) If you marked more than one traumatic event in Part 1, put a checkmark in the box next to the event that bothers you the most. If you marked only one traumatic event in Part 1, mark the same one below. Accident Disaster Non-sexual assault/someone you know Non-sexual assault/stranger Sexual assault/someone you know Sexual assault/stranger Combat Sexual contact under 18 with someone 5 or more years older Imprisonment Torture Life-threatening illness Other In the box below, briefly describe the traumatic event you marked above. Below are several questions about the traumatic event you just described above. (15) How long ago did the traumatic event happen? (circle ONE) 1 Less than1month 2 1 to 3 months 3 3 to 6 months 4 6 months to 3 years 5 3 to 5 years 6 More than 5 years For the following questions, circle Y for Yes or N for No. During this traumatic event: (16) Y N Were you physically injured? (17) Y N Was someone else physically injured? (18) Y N Did you think that your life was in danger? (19) Y N Did you think that someone else s life was in danger? (20) Y N Did you feel helpless? (21) Y N Did you feel terrified?

251 Group: WAD-RF, WAD-C Time Period: Subject ID#: Date: Part 3 Below is a list of problems that people sometimes have after experiencing a traumatic event. Read each one carefully and circle the number (0-3) that best describes how often that problem has bothered you IN THE PAST MONTH. Rate each problem with respect to the Motor Vehicle Collision you were involved in. 0 Not at all or only one time 1 Once a week or less / once in awhile 2 2 to 4 times a week / half the time 3 5 or more times a week / almost always (22) Having upsetting thoughts or images about the traumatic event that came into your head when you didn t want them to (23) Having bad dreams or nightmares about the traumatic event (24) Reliving the traumatic event, acting or feeling as if it was happening again (25) Feeling emotionally upset when you were reminded of the traumatic event (for example, feeling scared, angry, sad, guilty, etc.) (26) Experiencing physical reactions when you were reminded of the traumatic event (for example, breaking out in a sweat, heart beating fast) (34) Having trouble falling or staying asleep (35) Feeling irritable or having fits of anger (36) Having trouble concentrating (for example, drifting in and out of conversations, losing track of a story on television, forgetting what you read) (37) Being overly alert (for example, checking to see who is around you, being uncomfortable with your back to a door, etc.) (38) Being jumpy or easily startled (for example, when somewhat walks up behind you) (39) How long have you experienced the problems that you reported above? (circle ONE) 1 Less than one month 2 1 to 3 months 3 More than 3 months (40) How long after the traumatic event did these problems begin? (circle ONE) 1 Less than 6 months 2 6 or more months (27) Trying not to think about, talk about, or have feelings about the traumatic event (28) Trying to avoid activities, people, or places that remind you of the traumatic event (29) Not being able to remember an important part of the traumatic event (30) Having much less interest or participating much less often in important activities (31) Feeling distant or cut off from people around you (32) Feeling emotionally numb (for example, being unable to cry or unable to have loving feelings) Part 4 Indicate below if the problems you rated in Part 3 have interfered with any of the following areas of your life DURING THE PAST MONTH. Circle Y for Yes or N for No. (41) Y N Work (42) Y N Household chores and duties (43) Y N Relationships with friends (44) Y N Fun and leisure activities (45) Y N Schoolwork (46) Y N Relationships with your family (47) Y N Sex life (48) Y N General satisfaction with life (49) Y N Overall level of functioning in all areas of your life (33) Feeling as if your future plans or hopes will not come true (for example, you will not have a career, marriage, children, or a long life)

252 Group: WAD-RF, WAD-C Time Period: Pain Catastrophizing Scale Subject ID#: Date: Sullivan MJL, Bishop S, Pivik J. (1995) Age: Gender: Everyone experiences painful situations at some point in their lives. Such experiences may include headaches, tooth pain, joint or muscle pain. People are often exposed to situations that may cause pain such as illness, injury, dental procedures or surgery. Instructions: We are interested in the types of thoughts and feelings that you have when you are in pain. Listed below are thirteen statements describing different thoughts and feelings that may be associated with pain. Using the following scale, please indicate the degree to which you have these thoughts and feelings when you are experiencing pain. RATING MEANING Not at all To a slight degree To a moderate degree To a great degree All the time When I m in pain Number Statement 1 I worry all the time about whether the pain will end 2 I feel I can t go on 3 It s terrible and I think it s never going to get any better 4 It s awful and I feel that it overwhelms me 5 I feel I can t stand it anymore 6 I become afraid that the pain will get worse 7 I keep thinking of other painful events 8 I anxiously want the pain to go away 9 I can t seem to keep it out of my mind 10 I keep thinking about how much it hurts 11 I keep thinking about how badly I want the pain to stop 12 There s nothing I can do to reduce the intensity of the pain 13 I wonder whether something serious may happen Rating Copyright 1995 Michael J.L. Sullivan. Reproduced with permission. Source: Sullivan MJL, Bishop S, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess, 1995, 7:

253 Group: WAD-RF, WAD-C Time Period: S-LANSS Subject ID#: Date: 1. In the area where you have pain, do you also have pins and needles, tingling or prickling sensations? a) NO I don t get these sensations b) YES I get these sensations often 2. Does the painful area change colour (perhaps looks mottled or more red) when the pain is particularly bad? a) NO The pain does not affect the colour of my skin b) YES I have noticed that the pain does make my skin look different from normal 3. Does your pain make the affected skin abnormally sensitive to touch? Getting unpleasant sensations or pain when lightly stroking the skin might describe this. a) NO - The pain does not make my skin in that area abnormally sensitive to touch b) YES My skin in that area is particularly sensitive to touch 4. Does your pain come on suddenly and in bursts for no apparent reason when you are completely still? Words like electric shocks, jumping and bursting might describe this. a) NO My pain doesn t really feel like this b) YES I get these sensations often 5. In the area where you have pain, does your skin feel unusually hot like a burning pain? a) NO I don t have burning pain b) YES I get burning pain often 6. Gently rub the painful area with your index finger and then rub a non-painful area (for example, an area of skin further away or on the opposite side from the painful area). How does this rubbing feel in the painful area? a) The painful area feels no different from the non-painful area b) I feel discomfort, like pins and needles, tingling or burning in the painful area that is different from the non-painful area 7. Gently press on the painful area with your finger tip then gently press in the same way onto a non-painful area (the same non-painful area that you chose in the last question). How does this feel in the painful area? a) The painful area does not feel different from the non-painful area b) I feel numbness or tenderness in the painful area that is different from the non-painful area

254 POST-RFN QUESTIONNAIRE

255

256 Appendix 5: Results A. Study 1: Between Group Comparison (Healthy Controls, WAD_Non Responders & WAD_Responders. A1: Visual Analogue Scale (VAS) vs. Group Independent t-test analysis. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] WAD_NR WAD_R Combined Diff t 88 = 1.07 P = 0.29 A2: Neck Disability Index (NDI) vs. Group Independent t-test analysis. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] WAD_NR WAD_R Combined Diff t 88 = 1.36 P = 0.18 A3: Pain of predominantly neuropathic origin (s-lanss) vs. Group Mann-Whitney U analysis. Group Obs Rank Sum Expected WAD_NR WAD_R Combined z = 0.67 P = 0.51 A3.1: Proportion of individuals with elevated s-lanss ( 12) scores vs. Group Chi- Squared analysis. s-lanss score Group Total WAD_NR WAD_R < Total = 1.08 P =

257 A4: Pressure Pain Thresholds (PPT): Cervical Spine, Median Nerve and Tibialis Anterior Sites (log transformed data) vs. Group MANOVA analysis. Source Statistic df F (df1, df2) F Prob > F Group W P L R Residual 117 Total 119 Number of obs = 120; W = Wilks' lambda L = Lawley-Hotelling trace P = Pillai's trace R = Roy's largest root A4.1: PPT Post Hoc Analysis MANOVA test matrix: HC vs. Whiplash Groups. Source Statistic df F (df1, df2) F Prob > F Group W P L R Residual 117 Total 119 A4.2: PPT Post Hoc Analysis MANOVA test matrix: WAD_R vs. WAD_NR. Source Statistic df F (df1, df2) F Prob > F Group W P L R Residual 117 Total 119 A5: Cold pain thresholds (CPT) vs. Group Kruskal-Wallis analysis. Group Obs Rank Sum Mean Rank Group Diff LSD 1 = HC (1,2) 37.2 * 2 = WAD_NR (1,3) 44.4* 3 = WAD_R (2,3) = 31.1 P = *P >

258 A6: Heat pain thresholds (HPT) vs. Group Kruskal-Wallis analysis. Right Side of Neck Group Obs Rank Sum Mean Rank Group Diff LSD 1 = HC (1,2) 37.4* 2 = WAD_NR (1,3) 39.7* 3 = WAD_R (2,3) = 28.2 P = *P > 0.05 Left Side of Neck Group Obs Rank Sum Mean Rank Group Diff LSD 1 = HC (1,2) 30.7* 2 = WAD_NR (1,3) 32.5* 3 = WAD_R (2,3) = 18.9 P = *P > 0.05 A7: Brachial Plexus Provocation Test (BPPT) elbow extension range of motion (ROM) vs. Group one-way ANOVA analysis of log transformed data. Source SS Df MS F Prob > F Between groups Within groups Total = 31.1 P = A7.1: Post hoc Analysis BPPT. Row Mean -> Column Mean HC WAD_NR WAD_NR P value WAD_R P value A8: Nociceptive Flexion Reflex (NFR) vs. Group one-way ANOVA analysis of log transformed data. Source SS df MS F Prob > F Between groups Within groups Total = 31.1 P =

259 A8.1 Post hoc analysis NFR threshold. Row Mean -> Column Mean WAD_NR P value WAD_R P value HC WAD_NR A9: Range of motion (ROM: flexion, extension, side flexion left and right, rotation left and right) vs. Group MANOVA analysis. Source Statistic df F (df1, df2) F Prob > F Group W Residual 117 Total 119 P L R Number of obs = 120; W = Wilks' lambda L = Lawley-Hotelling trace P = Pillai's trace R = Roy's largest root A9.1: Post hoc analysis ROM MANOVA test matrix: HC vs. Whiplash Group s. Source Statistic df F (df1, df2) F Prob > F Group W P L R Residual 117 A9.2: Post hoc analysis ROM - MANOVA test matrix: WAD_R vs. WAD_NR. Source Statistic df F (df1, df2) F Prob > F Group W P L R Residual

260 A10: EMG of the superficial neck musculature (22mmHg, 24mmHg, 26mmHg, 28mmHg and 30mmHg) vs. Group MANOVA analysis. Source Statistic Df F (df1, df2) F Prob > F Group W Residual 116 Total 118 P L R A10.1: Post hoc analysis: EMG MANOVA test matrix: HC vs. Whiplash Group s. Source Statistic Df F (df1, df2) F Prob > F Group W P L R Residual 116 A10.2: Post hoc analysis: EMG MANOVA test matrix: WAD_R vs. WAD_NR. Source Statistic Df F (df1, df2) F Prob > F Group W P L R Residual 116 A11: Psychological distress (GHQ-28) vs. Group Kruskal-Wallis analysis. Group Obs Rank Sum Mean Rank Group Diff LSD 1 = HC (1,2) 49.9* 2 = WAD_NR (1,3) 41.8* 3 = WAD_R (2,3) = 38.2 P = *P >

261 A11.1: Proportion of individuals with psychological distress (GHQ-28) vs. Group Chisquared analysis. GHQ-28 score Group Total HC WAD_NR WAD_R < Total Between Groups Between Whiplash Groups 2 = 30.1 P < = P = 0.86 A12: Pain catastrophization (PCS) vs. Group (WAD_NR & WAD_R) Mann-Whitney U analysis. Group Obs Rank Sum Expected WAD_NR WAD_R Combined z = 2.7 P = A12.1: Proportion of individuals in the two whiplash groups (WAD_NR & WAD_R) with elevated ( 30) PCS scores Chi-squared analysis. PCS Score Group Total WAD_NR WAD_R < Total = 12.2 P = A13: Proportion of individuals in the two whiplash groups (WAD_NR & WAD_R) that fulfill the PTSD criteria (utilizing the PDS scale) Chi-squared analysis. Fulfill PDS Group Total Criteria? WAD_NR WAD_R No Yes Total = 1.90 P =

262 A13.1: Post traumatic stress severity (PDS) scores vs. Group (WAD_NR & WAD_R) Mann-Whitney U analysis. Group Obs Rank Sum Expected WAD_NR WAD_R Combined z = 1.69 P =

263 B. Study 2: Participants Undergoing Radiofrequency Neurotomy Longitudinal Analysis of Physical Measures B1: VAS vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B1.1: Post-hoc analysis: VAS vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B2: NDI vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B2.1: Post-hoc analysis: NDI vs. Time. Source SS df MS F Prob > F Between groups Within groups Total

264 B3: log Cervical Spine PPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B3.1: Post-hoc analysis: log Cervical Spine PPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B3.2: log Cervical Spine PPT vs. Group (t(2): prior to RFN) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = 5.29 P = B3.3: log Cervical Spine PPT vs. Group (t(4): post-rfn) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 2.26 P =

265 B4: log Median Nerve PPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B4.1: Post-hoc analysis: log Median Nerve PPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B4.2: log Median Nerve PPT vs. Group (t(2): prior to RFN) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 1.02 P = B4.3: log Median Nerve PPT vs. Group (t(4): post-rfn) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 1.02 P =

266 B5: log Tibialis Anterior PPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B5.1: Post-hoc analysis: log Tibialis Anterior PPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B5.2: log Tibialis Anterior PPT vs. Group (t(2): prior to RFN) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 5.86 P = B5.3: log Tibialis Anterior PPT vs. Group (t(4): post-rfn) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 1.02 P =

267 B6: log Nociceptive Flexion Reflex Threshold (NFR) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B6.1: Post-hoc analysis: log NFR vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B6.2: log NFR vs. Group (t(2): prior to RFN) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = 2.97 P = B6.3: log NFR vs. Group (t(4): post-rfn) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 0.67 P =

268 B7: log Brachial Plexus Provocation Test (BPPT) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B7.1: Post-hoc analysis: log BPPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B7.2: log BPPT vs. Group (t(2): prior to RFN) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = -9.2 P = B7.3: log BPPT vs. Group (t(4): post-rfn) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 67 = P =

269 B8: Cold Pain Threshold (CPT) vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 18.5 Kendall 0.17 P Value B8.1: Post hoc Analysis Wilcoxon signed-rank test. Time Period P value P value P value B8.2: CPT vs. Group (t(2): prior to RFN) Mann Whitney U test. Group Obs Rank Sum Expected HC WAD_RF Combined z = P = B8.3: CPT vs. Group (t(4): post-rfn) Mann Whitney U test. Group Obs Rank Sum Expected HC WAD_RF Combined z = P = B9: Heat Pain Threshold (HPT) vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 34.8 Kendall 0.17 P Value

270 B9.1: Post hoc Analysis Wilcoxon signed-rank test. Time Period P value P value P value B9.2: HPT vs. Group (t(2): prior to RFN) Mann Whitney U test. Group Obs Rank Sum Expected HC WAD_RF Combined z = P = B9.3: HPT vs. Group (t(4): post-rfn) Mann Whitney U test. Group Obs Rank Sum Expected HC WAD_RF Combined z = 1.37 P = 0.17 B10: Range of Motion (ROM) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total

271 B10.1: Post-hoc analysis: ROM vs. Time. Source SS df MS F Prob > F Between groups Within groups Total B10.2: ROM vs. Group (t(2): prior to RFN) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = 15.4 P = B10.3: ROM vs. Group (t(4): post-rfn) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = 6.12 P = B11: Cranio-cervical EMG (22mmHg) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total

272 B11.1: EMG (22mmHg) vs. Group (t(2): prior to RFN) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = P = B11.2: EMG (22mmHg) vs. Group (t(4): post-rfn) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 77 = P = B12: Cranio-cervical EMG (24 mmhg) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B12.1: Post-hoc analysis: 24mmHg EMG vs. Time. Source SS df MS F Prob > F Between groups Within groups Total

273 B12.2: EMG (24mmHg) vs. Group (t(2): prior to RFN) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = P = B12.3: EMG (24mmHg) vs. Group (t(4): post-rfn) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = P = 0.69 B13: Cranio-cervical EMG (26 mmhg) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B13.1: Post-hoc analysis: 26mmHg EMG vs. Time. Source SS df MS F Prob > F Between groups Within groups Total

274 B13.2: EMG (26mmHg) vs. Group (t(2): prior to RFN) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = P = B13.3: EMG (26mmHg) vs. Group (t(4): post-rfn) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 77 = P = 0.45 B14: Cranio-cervical EMG (28 mmhg) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B14.1: Post-hoc analysis: 28mmHg EMG vs. Time. Source SS df MS F Prob > F Between groups Within groups Total

275 B14.2: EMG (28mmHg) vs. Group (t(2): prior to RFN) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = P = B14.3: EMG (28mmHg) vs. Group (t(4): post-rfn) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = P = 0.49 B15: Cranio-cervical EMG (30 mmhg) vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Subject Time Residual Total B15.1: EMG (30mmHg) vs. Group (t(2): prior to RFN) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 81 = P =

276 B15.2: EMG (30mmHg) vs. Group (t(2): post-rfn) Independent t-test. Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] HC WAD_RF Combined Diff t 78 = P =

277 C. Study 3: Participants Undergoing Radiofrequency Neurotomy Longitudinal Analysis of Psychological Measures C1: GHQ-28 vs. Time Chi-squared analysis Time -> GHQ-28 Score Total < Total = P = C1.1: GHQ-28 vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 13.5 Kendall 0.13 P Value C1.2: Post hoc Analysis Wilcoxon signed-rank test. Time P value P value P value C2.1: GHQ-28 (Somatic subscale) vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 11.7 Kendall 0.11 P Value

278 C2.2: Post hoc Analysis Wilcoxon signed-rank test. Time P value P value P value C3.1: GHQ-28 (Anxiety/Sleeplessness subscale) vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 7.99 Kendall 0.08 P Value C3.2: Post hoc Analysis Wilcoxon signed-rank test. Time P value P value P value C4.1: GHQ-28 (Social Dysfunction subscale) vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 14.5 Kendall 0.14 P Value

279 C4.2: Post hoc Analysis Wilcoxon signed-rank test. Time P value P value P value C5.1: GHQ-28 (Severe Depression subscale) vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 3.97 Kendall 0.04 P Value 0.14 C5.2: PCS vs. Time Chi-squared analysis Time -> PCS Score Total < Total = 3.65 P = 0.30 C6.1: PCS vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman Kendall 0.20 P Value C6.2: Post hoc Analysis Wilcoxon signed-rank test. Time P value P value P value

280 C7: PDS (fulfilling PTSD criteria) vs. Time Chi-squared analysis Time -> PDS Score Total Not Fulfilling PTSD criteria Fulfilling PTSD criteria Total = 4.67 P = 0.20 C7.1: PDS Severity Score vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 1.90 Kendall 0.02 P Value 0.39 C7.2: PDS Symptom Score vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 2.24 Kendall 0.02 P Value

281 D. Study 4: Return of Pain Longitudinal Analyses D1: NDI vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline Disability Subject Time Residual Total D1.1: Post-hoc analysis: NDI vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

282 D2: log Cervical Spine PPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logpptc Subject 0 0 Time Residual Total D2.1: Post-hoc analysis: log Cervical Spine PPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

283 D3: log Median Nerve PPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logpptm Subject Time Residual Total D3.1: Post-hoc analysis: log Median Nerve PPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

284 D4: log Tibialis Anterior PPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logpptt Subject Time Residual Total D4.1: Post-hoc analysis: log Tibialis Anterior PPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

285 D5: log NFR vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline lognfr Subject Time Residual Total D5.1: Post-hoc analysis: log NFR vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

286 D6: log BPPT vs. Time repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logbppt Subject Time Residual Total D6.1: Post-hoc analysis: log BPPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

287 D7: CPT vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline Cold Subject Time Residual Total D7.1: Post-hoc analysis: CPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

288 D8: HPT vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline Heat Subject Time Residual Total D8.1: Post-hoc analysis: HPT vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

289 D9: ROM vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline ROM Subject Time Residual Total D9.1: Post-hoc analysis: ROM vs. Time. Source SS df MS F Prob > F Between groups Within groups Total Time P value P value

290 D10: EMG (22mmHg) vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logdnf22 Subject Time Residual Total D10.1: Post-hoc analysis: EMG (22mmHg) vs. Time. Source SS df MS F Prob > F Between groups Within groups Total D11: EMG (24mmHg) vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logdnf Subject Time Residual Total

291 D12: EMG (26mmHg) vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logdnf26 Subject Time Residual Total D12.1: Post-hoc analysis: EMG (26mmHg) vs. Time. Source SS df MS F Prob > F Between groups Within groups Total D13: EMG (28mmHg) vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logdnf Subject Time Residual Total

292 D13.1: Post-hoc analysis: EMG (28mmHg) vs. Time. Source SS df MS F Prob > F Between groups Within groups Total D14: EMG (30mmHg) vs. Time one-way repeated measures ANOVA analysis. Source Partial SS df MS F Prob > F Model Age Gender Baseline logdnf30 Subject Time Residual Total D15: GHQ-28 vs. Time repeated measures Friedman analysis. Friedman v1-v42 Friedman 23.2 Kendall 0.28 P Value D15.1: Post hoc Analysis Wilcoxon signed-rank test. Time P value 3 P value

293 D16: PCS vs. Time repeated measures Friedman analysis. Friedman v1-v42 Friedman Kendall 0.16 P Value D16.1: Post hoc Analysis Wilcoxon signed-rank test. Time P value P value D17: PDS (fulfilling PTSD criteria) vs. Time Chi-squared analysis. Time -> PDS Score Total Not Fulfilling PTSD criteria Fulfilling PTSD criteria Total = 4.42 P = 0.11 D17.1: PDS Severity Score vs. Time repeated measures Friedman analysis. Friedman v1-v42 Friedman 2.39 Kendall 0.03 P Value 0.30 D17.2: PDS Symptom Score vs. Time repeated measures Friedman analysis. Friedman v1-v53 Friedman 2.24 Kendall 0.02 P Value

294 E: Study 5: Predictors of Cervical Radiofrequency Neurotomy Success E1.1: Proportion of individuals by gender in the two whiplash groups (Success and Less Successful) Chi-squared analysis RFN Group Total Successful? Female Male Yes No Total = 0.57 P = 0.57 E1.2: Age vs. Group (Success and Less Successful) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] Success Less Success Combined Diff t 51 = 0.76 P = 0.45 E1.3: Duration of Symptoms vs. Group (Success and Less Successful) Mann Whitney U analysis Group Obs Rank Sum Expected Success Less Success Combined z = -1.2 P = 0.25 E1.4: Pain vs. Group (Success and Less Successful) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] Success Less Success Combined Diff t 51 = P =

295 E1.5: Disability vs. Group (Success and Less Successful) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] Success Less Success Combined Diff t 51 = -2.2 P = 0.03 E1.6: logpptc vs. Group (Success and Less Successful) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] Success Less Success Combined Diff t 51 = 1.01 P = 0.32 E1.7: logppttibant vs. Group (Success and Less Successful) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] Success Less Success Combined Diff t 51 = 0.11 P = 0.91 E1.8: Cold vs. Group (Success and Less Successful) Independent t-test Group Obs Mean Std. Err. Std. Dev. [95% Conf. Interval] Success Less Success Combined Diff t 51 = P =

296 E1.9: Pain catastrophization (PCS) vs. Group (Success and Less Successful) Mann- Whitney U analysis. Group Obs Rank Sum Expected Success Less Success Combined z = P = E1.10: Post Traumatic Stress Severity (PDS) vs. Group (Success and Less Successful) Mann-Whitney U analysis. Group Obs Rank Sum Expected WAD_NR WAD_R Combined z = P = 0.39 E2.1: Univariate Logistic Regression: Predictor Variable = Pain OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi E2.2: Univariate Logistic Regression: Predictor Variable = Disability OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi E2.3: Univariate Logistic Regression: Predictor Variable = Pain Catastrophization OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi

297 E2.4: Univariate Logistic Regression: Predictor Variable = LogPPTcervical OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi E2.5: Univariate Logistic Regression: Predictor Variable = LogPPTtibant OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi E2.6: Univariate Logistic Regression: Predictor Variable = Cold OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi E2.7: Univariate Logistic Regression: Predictor Variable = Post Traumatic Stress Severity OR Std. Err. Z P > Z [95% Conf. Interval] Pain LR chi Prob > chi E3: Correlations between Predictor Variables Pain Catastrophization P Value Post Traumatic Stress Severity P Value Disability P Valeu Pain Catastrophization * * Post Traumatic Stress Severity * Disability 1.00 E4.1: Stepwise Multivariable Logistic Regression: Predictor Variable = Disability OR Std. Err. Z P > Z [95% Conf. Interval] Disability LR chi Prob > chi

298 E4.2: Stepwise Multivariable Logistic Regression: Predictor Variable = Pain Catastrophization OR Std. Err. Z P > Z [95% Conf. Interval] PCS LR chi Prob > chi E5.1: Diagnostic Accuracy in Predicting Success for Predictor Variable = Pain Catastrophization (PCS) True ( Success ) Classified by PCS + - Total Total Classified + if predicted Pr(D) >=.5 True D defined as GROCcut!= Sensitivity Pr( + D) 95.00% Specificity Pr( - ~D) 23.08% Positive predictive value Pr( D +) 79.17% Negative predictive value Pr(~D -) 60.00% False + rate for true ~D Pr( + ~D) 76.92% False - rate for true D Pr( - D) 5.00% False + rate for classified + Pr(~D +) 20.83% False - rate for classified - Pr( D -) 40.00% Correctly classified 77.36%

299 E5.2: ROC Curve for Predictor Variable = PCS E5.3: Diagnostic Accuracy in Predicting Success for Predictor Variable = Disability True ( Success ) Classified by Disability + - Total Total Classified + if predicted Pr(D) >=.5 True D defined as GROCcut!= Sensitivity Pr( + D) 97.50% Specificity Pr( - ~D) 23.08% Positive predictive value Pr( D +) 79.59% Negative predictive value Pr(~D -) 75.00% False + rate for true ~D Pr( + ~D) 76.92% False - rate for true D Pr( - D) 2.50% False + rate for classified + Pr(~D +) 20.41% False - rate for classified - Pr( D -) 25.00% Correctly classified 79.25%